‘PARKINSON'S DISEASE’

A Practice School report submitted to the Institute of Pharmacy,

Bundelkhand University, Jhansi in partial fulfillment of the award of the
degree of

Bachelor of Pharmacy

2023-2024

Submitted To: Submitted by:

DR. SUNEEL KUMAR NIRANJAN SHIVANGI PANCHAL
Assistant Professor B. Pharm 8th sem
Institute of Pharmacy, Roll No. 211251016507
Bundelkhand University,
Jhansi (U.P.)

INSTITUTE OF PHARMACY
BUNDELKHAND UNIVERSITY JHANSI
 INSTITUTE OF PHARMACY
BUNDELKHAND UNIVERSITY JHANSI

2023-2024

Certificate

This is to certify that the project entitled “PARKINSON'S DISEASE”

submitted in partial fulfillment of the requirement for the Bachelor of
Pharmacy, Institute of Pharmacy, Bundelkhand University, Jhansi is a
bonafide work carried out by SHIVANGI PANCHAL during the academic
session 2023-2024.

DR. PEEYUSH BHARDWAJ

Date: Head of Department
Institute of Pharmacy
B.U. Jhansi

INSTITUTE OF PHARMACY
i
 BUNDELKHAND UNIVERSITY JHANSI

2023-2024

Certificate

This is to certify that the project entitled “PARKINSON'S DISEASE’”

submitted in partial fulfillment of the requirement for the Bachelor of
Pharmacy, Institute of Pharmacy, Bundelkhand University, Jhansi is a
bonafide work carried out by SHIVANGI PANCHAL during the academic
session 2023-2024.

DATE: GUIDE:
DR. SUNEEL KUMAR NIRANJAN
ASSISTANT PROFESSOR
INSTITUTE OF PHARMACY
B.U. JHANSI
INSTITUTE OF PHARMACY
ii
 BUNDELKHAND UNIVERSITY JHANSI

2023-2024

DECLARATION

This is to certify that the project entitled “PARKINSON'S DISEASE’” is

prepared by me under the direct guidance and supervision of DR. SUNEEL
KUMAR NIRANJAN (Asst. Prof.) Institute of Pharmacy, Bundelkhand
University, Jhansi. The same is submitted to Bundelkhand University, Jhansi
in partial fulfillment of requirement for the award of degree of Bachelor of
Pharmacy.

I further declare that I have not submitted this project report previously for the
award of any degree or diploma to me.

SHIVANGI PANCHAL
ACKNOWLEDGEMENT
iii
Firstly, I would like to thank GOD. Most gracious and most merciful the
omnipotent the omniscient who gave me the strength to complete this work,
without his generous blessing it was not possible to complete this work.

Words are indeed insufficient to express the depth of profound gratitude to

Dr. Peeyush Bhardwaj Sir (H.O.D) of Institute of Pharmacy, Bundelkhand
University, Jhansi (U.P.) for his valuable guidance, constructive criticism, and
encouragement during the entire course.

I am extremely grateful to DR. SUNEEL KUMAR NIRANJAN (Asst. Prof.)

Institute of Pharmacy, Bundelkhand University Jhansi (U.P) to be
thoroughly involved in solving my problems during the entire academic

session and for magnanimity in helping me to complete my choose project "

PARKINSON'S DISEASE’" at Institute of Pharmacy, Bundelkhand
University, Jhansi.

Above all, I express my deep-hearted gratitude to my esteemed parents,

whose emotion and moral fragrance always empowered me to carry on my
studies.

SHIVANGI PANCHAL

iv
 INDEX

S.NO. CONTENT PG.NO.

CERTIFICATE i-ii
DECLARATION iii
ACKNOWLEDGEMENT iv
INDEX v
1. Introduction 1

2. Enzymes involved in APP processing 6

3. Degradation of alpha beta 9

4. Other Enzymes 11
• Protease
• Microglia
5. Clearence of Amyloid 13

6. Current Strategy for Delivery of Alzheimer Drug Targeting beta 13

Amyloid
• Approaches
7. Blood Brain Barrier 14

8. Nanoparticles 21
9. Concluding Remark and Future Perspective 22
10. References 24

v
 INTRODUCTION

Alzheimer’s disease [AD] most common cause of dementia. The majority of

cases come from old age 65 [LATE ONSET] but it can also affect people 30 and
40s [EARLY ONSET]. Approx1% to 2% of Alzheimer’s is inherited through
autosomal dominance. Dementia due to AD is a classical symptom. The
International Alzheimer’s disease report estimates that 47 million people
worldwide suffer from AD and is estimated to increase by 131 million in 2050.
India has the lowest rate of AD.

It is biologically defined by the presence of specific neuropathologically by

extracellular deposition of beta-amyloid (Ab) in the form of diffuse and neuritic
plaques and the presence of intraneuronal neurofibrillary tangles (NFTs) and
neuropil threads within dystrophic neurites consisting of aggregated
hyperphosphorylated tau protein[1]. Although the exact source of the disease is
not known. Alzheimer's disease is caused by misfolding of proteins and
consequently, aggregation of proteins in the brain [16].

Role Of Beta-Amyloid: The accumulation of extracellular glittery plaque

mediated by βamyloid intracellular neurofibriltangle (NFT) and synaptic
degeneration. This mainly occurs in the neocortex (which comprises the largest
part of the cerebral cortex), hippocampus, and other subcortical regions which
are necessary for cognitive function. Hence they can be good markers for
Alzheimer’s prediction[2]. In mammals, APP belongs to a small gene family
that includes the genes encoding the APP-like proteins (APLPs) APLP1 and
APLP2. The amyloid precursor protein (APP) is a type 1 single-pass protein
with large extracellular domains and a short cytoplasmic tail which is expressed
very high in the brain and metabolized in a rapid and very complex manner.
APP and APLPs share a conserved region (including their E1 and E2 domains)
[3].E1 and E2 independently folded subdomains and the intrinsically disordered
C-terminal APP intracellular domain (AICD) which adopt specific folds upon
binding to certain interactors. Only APP generates an amyloidogenic fragment
owing to sequence divergence at the internal beta-amyloid site. APP is encoded
by a single gene. Alternate splicing of APP transcript generates 8 isoforms, of
which 3 is most common; the 695 amino acid form, which is expressed mainly
in the CNS, and the 751 and 770 amino acid forms present everywhere[4]. The
Amyloid-β sequence is found only in APP, not in APLPs[3]

1
Biological Function Of APP: APP family members are involved include
nervous system development, formation, and function of the neuromuscular
junction, synaptogenesis, dendritic complexity, spine density, axonal growth,
and guidance, and synaptic functions including synaptic plasticity, learning, and
memory[3]

The Domain Structure of APP Family Protein: Amyloid precursor protein

(APP) is a type I single-pass transmembrane protein with a large extracellular
domain and a short cytoplasmic tail. X-ray structural information is available
for the extracellular, independently folded E1 and E2 subdomains; nuclear
magnetic resonance structures were solved for C-terminal fragment-β (CTFβ)
and the cytoplasmic tail. for the structure of isoform APP695; domains with
known atomic structures (including E1 and E2) and the transmembrane domain
(TMD) are depicted as ribbons and secretase cleavage sites. E1 can be
subdivided into the growth factor-like domain (GFLD), which contains the first
heparin-binding domain (HBD), and the copper-binding domain (CuBD);
GFLD and CuBD are both stabilized by several disulfide bridges. In the major
neuronal APP isoform APP695, the acidic domain (AcD; which is rich in
glutamic acid and aspartic acid) is most likely to be unfolded and highly
flexible and directly links E1 to E2.

The longer variants, APP751 and APP770, result from differential splicing of
one or two exons encoding the Kunitz-like protease inhibitor domain (KPI) and
the short Ox-2 antigen domain. APP695 lacks the KPI and Ox-2 domains, and
APP751 lacks only the Ox-2 domain. E2, in turn, contains a second HBD and a
RERMS motif (not shown) that has been implicated in the trophic functions.
The cleavage sites for α-secretase and β-secretase are found in the flexible
juxtamembrane region that links E2 to the TMD, whereas γ-secretase cuts
within the TMD. The TMD directly interacts with cholesterol, which is known
to modulate APP processing.

Post-translational modifications, including Oglycosylation and N-glycosylation,

chondroitin sulfate glycosaminoglycan modifications as well as sialyation
further influence the structure and function of APP. APP contains an iron-
binding site that has been suggested to possess ferroxidase activity[5]. In figure
part b other APP family and APP structures domain. All APP families have
conserved E1 and E2 domain and AcD. β Amyloid is a unique domain to
APP[3]

2
 Figure 1

Figure 2

Generation Of β-Amyloid: β-amyloid is a small hydrophobic peptide(approx-

4kDa). The Aβ peptide is a 38- to 43- amino acid residue peptide[6]. Amyloid-β
3
is generated from APP by sequential cutting of beta(β) and gamma(γ) secretase.
Aβ43 and Aβ42 are highly pathogenic. Amyloid plaque is a pathological
hallmark in AD. Preplaque aggregation of Aβ using an aggregation-specific
antibody is directly associated with ultrastructural evidence of subcellular
pathology [7].

Processing Of APP: Processing can be done by two pathways

1. Amyloidogenic Pathway- Generate β-amyloid.
2. Non-Amyloidogenic Pathway

Amyloidogenic processing of APP begins with beta(β) secretase cleavage,

which results in the production of the large N-terminal ectodomain amyloid
precursor protein beta (sAPPβ). The remaining C-terminal fragment (CTF),
which is 99 amino acids long, can subsequently be cleaved further by γ -
secretase, resulting in amyloid-β and a soluble APP intracellular domain
(AICD).

C99 occurs at multiple sites. APP is first cleaved at the ε -site, either at the
Thr645-Leu646 bond or at the Leu646-Val647 bond, resulting in soluble
AICD50 or AICD49. The remaining membrane bound fragment is then cleaved
at every third residue from the -site to the ε -site, resulting in the product lines
A49→A46→A43→A40 and A48→A45→A42→A38.

The production of Amyloid-β is prevented in the non-amyloidogenic pathway

because APP is first broken by α- secretase within the A sequence near the
ectoplasmic side of the plasma membrane. The cleavage of APP by α-secretase
releases the N-terminal ectodomain, sAPP. leaving an 83amino-acid C-terminal
membrane-bound fragment on the cell surface (C83). In a similar way to the
amyloidogenic route, the residual C83 fragment can be digested by α -secretase.

Figure-3

4
Figure-3 - The processing of an APP is depicted in this diagram. APP is broken
by α -secretase in the non-amyloidogenic route, resulting in the secreted sAPPα
fragment. APP is cleaved by βsecretase in the amyloidogenic pathway, resulting
in sAPPβ.γ-secretase then cleaves the remaining C-terminal membrane-bound
stubs, C83 and C99, releasing the APP intracellular domain (AICD) and p3 or
Aβ.γ -Secretase cleaves APP at the ε-site initially, then at every third residue
(shown by arrowheads) in the direction of the γ -site.

Figure-4-The alpha- or beta-secretases cleave the non-amyloidogenic and

amyloidogenic pathways of APP processing. The non-amyloidogenic route
yields sAPP-alpha and C83 after cleavage by alpha-secretase (left). sAPP-beta
and C99 are produced through beta-secretase cleavage (the amyloidogenic
route) (right). Gamma-secretase cleaves C83, resulting in AICD and p3 (not
shown). Gamma-secretase also cleaves C99, resulting in AICD and Amyloid-
beta (right) (SPIES et al., 2012)
5
Enzymes Involved in APP Processing

Αlpha-Secretase: Family of proteolytic family[9]. The Aβ domain of APP is

broken by an alpha-secretase in the non-amyloidogenic pathway. Alpha
secretases are a family of proteolytic enzymes that cleave amyloid precursor
protein (APP) in its transmembrane region, preventing complete Aβ from being
deposited. The Aβ sequence between lysine 16 and leucine 17 is cleaved by the
first protease, which is followed by an unknown carboxypeptidase, which yields
sAPP and the membrane-tethered C83. sAPP has been identified as a
neurotrophic and neuroprotective factor. This cleavage mediated by APP alpha-
secretase occurs constitutively (constitutive alphasecretase) and can be activated
above its constitutive level by a heterogeneous group of substances[10]
Therefore α-secretase cleavage of APP is beneficial, not only by precluding the
formation of Aβ peptides but also by protecting against neurotoxic agents. A
decrease in αsecretase activity is seen in AD patients.

Members of the disintegrin and metalloproteinase families of proteins have

secretase activity (ADAM). These proteins have a prodomain, a
metalloproteinase domain, a disintegrin domain, a cysteine-rich region, and an
epidermal growth factor repeat region and are membrane-anchored or secreted.
Members of the ADAM protein family have a role in the activation of various
signaling pathways. The α-secretase activity is principally controlled by
ADAM10 and ADAM17 also known as TACE (Tumor necrosis factor α)
(TNFα). ADAM17 is thought to be in charge of the inducible-secretase activity,
whereas ADAM10 is in charge of constitutive activity and may also be involved
in an inducible activity. ADAM 10 can be activated by various cell-surface
receptors, which activate PKC, mitogen-activated protein kinases,
phosphoinositide 3-kinase, and calcium signaling.

Beta-Secretase: Secretase is an aspartyl protease that cleaves the Met597-

Asp598 bond in APP, which is the first rate-limiting step in the synthesis of Aβ.
BACE1 (β-site APP-cleaving enzyme) and BACE2 are two β-secretases that
have been discovered. BACE1 is a single-domain integral protein having an
active site on the membrane's ectoplasmic side. Intracellular calcium
homeostasis disruption may stimulate BACE-1 genetic expression by
stimulating the nuclear factor of activated T-cells type 1 (NFAT1), resulting in
Aβ overproduction[11]

BACE1 is a type I transmembrane protein, which distinguishes it from other

cathepsin D and E like peptidases that lack a transmembrane domain. BACE1 is
6
abundant in numerous neuronal cell types and is expressed broadly throughout
the brain, notably in neurons, oligodendrocytes, and astrocytes. BACE1 was
found in healthy synaptic terminals and dystrophic neurites surrounding
amyloid-β (Ab) plaques at the subcellular level, where it was found on the
plasma membrane and in endosomal compartments. BACE1 is related to
BACE2, another pepsin-family membranebound secretase. Both proteases have
similar structural domains and share 59% of their amino acid sequence. Both
secretases include two aspartic acid residues in their extracellular domains and
helical transmembrane domains with 21 residues and small cytoplasmic C-
terminal domains. The secretases are known to be glycosylated on multiple
asparagine residues, and they have three disulfide bonds to assist maintain their
tertiary structure. BACE1 secretase undergoes posttranslational changes that are
crucial for lipid raft localization, phosphorylation for cellular trafficking, and
ubiquitination for destruction. Both BACE1 and BACE2 are expressed in the
brain, although BACE2 is far less common. BACE2 is thought to be more
active in peripheral tissues, such as melanocytes and pancreatic β cells.

The soluble N-terminus of APP is released when β-secretase cleaves it, but the
C-terminal fragment (CTF-b orC99) stays linked to the membrane.

The pathophysiology of Alzheimer's disease (AD) has not yet been linked to
BACE1 gene mutations. Mutations in APP near b-secretase sites, on the other
hand, are thought to be either protective or induce early-onset Alzheimer's
disease. The Swedish mutation (K670M671 to N670L671 at the cleavageP2-P1
subsite) promotes the early onset of AD by increasing APP processing at the b
site 10- to 50-fold[12].

γ-Secretase: The γ-secretase complex is a founding member of the

intramembrane-cleaving proteases (I-CLiPs) family, which hydrolyze substrates
in the lipid bilayer’s hydrophobic environment. I-CLiPs are proteins that cut
inside their substrates' transmembrane domains (TMD) and serve a variety of
important roles in biology. γ-Secretase was originally identified as an activity
that cleaves the TMD of the amyloid precursor protein (APP) to create the
amyloid -β peptide (Aβ) that is accumulated as plaques in the brain in
Alzheimer's disease[13]. γ-Secretase is an aspartyl protease. The γ-secretase
complex is known as "the membrane of the proteasome."

The enzyme is made up of a protein complex that includes Anterior Pharynx

defective-1(APH-1), nicastrin, presenilin-1 or -2 (PS1 or PS2), and presenilin
enhancer-2 (PEN-2). Within TM6 and TM7, the catalytic site is composed of
7
two highly conserved aspartate residues (Asp257 and Asp385 in human PS1).
PS1 is a 9 TM protein that has been found to contain the enzyme's active site.
Within the cytosolic loop between TM6 and TM7, both presenilins undergo
endoproteolysis, yielding a C- and an N-terminal fragment. The two fragments
form a stable heterodimer, which is presenilin's active conformation. Presenilin-
1 and 2 (PSEN1 and PSEN2, respectively) were revealed to have additional
FAD(Familial Alzheimer’s Disease) missense mutations[13]

Familial Alzheimer's Disease is a kind of Alzheimer's Disease that has been

proven to be connected to genes by doctors.

Nicastrin has a single TM and a substantial ectodomain that may serve as a

gatekeeper to the PS active site. Nicastrin is also involved in substrate binding
and is important for the assembly of the γ-secretase complex. The roles of APH-
1 and PEN-2 are still being researched.

However, PEN-2 has been demonstrated to stabilize the final complex, while
APH1 is involved in the complex's construction and has also been linked to
substrate recognition. There are two APH-1 homologs, each of which can go
through alternative splicing to produce a short or long isoform. The presence of
several isoforms in the γ-secretase complex appears to have an impact on its
substrate selectivity.

γ-secretase is mostly found at the plasma membrane and in the

endosomal/lysosomal system when it is mature and proteolytically active. The
subcellular distribution of the enzyme complex has been demonstrated to
influence APP-cleavage, with longer APP intracellular domain (AICDs) being
generated at the plasma membrane than in endosomes. γ-secretase has over 90
known substrates, including Notch, N-cadherin, and ephrin B, in addition to
APP, and the list is constantly expanding. The majority of the substrates are type
I transmembrane proteins that are cleaved by another protease in the
ectodomain[14]

8
 Figure 5- Intermembrane proteolysis by the γ-secretase complex[13]

Degradation Of Aβ: The proteasome and the lysosome are two of the most
important mechanisms that mediate cellular proteolysis. The two systems keep
cellular homeostasis in check by digesting a variety of proteins, including
defective or misfolded proteins with varying lifespans, and they play a key role
in controlling protein concentrations inside the cell.

During cellular damage, a family of Ca++-activated cysteine proteases known

as calpains is triggered. Second, quick post-translational processes activate a set
of cystolic cysteine-dependent aspartate-directed proteases (caspases), which
initiate a cascade of events that are indicative of programmed cell death or
apoptosis.

UPS (Ubiquitin-Proteosome System): The proteasome is a multi-catalytic,

multisubunit protease complex that uses ubiquitin homopolymers as a signal to
degrade proteins in an ATP-dependent mechanism. The 26S proteasome is the
most prevalent kind in mammals, with a proteolytic 20S core component
9
flanked by two 19S regulatory subunits. The hollow center of the protease
complex allows proteins to enter and be destroyed.
• By binding its cysteines, the E1 "ubiquitin-activating" enzyme activates
ubiquitin.
• The ubiquitin is subsequently passed on to one of the several E2
"ubiquitin-conjugating" enzymes. A cysteine binds the C-terminus of
ubiquitin once again.
• E3 "ubiquitin ligase" enzymes are one of the hundreds that transport
ubiquitin to its ultimate protein target. The C-terminus of ubiquitin forms
a covalent peptide connection with the NH2 side chain of lysine in the
target.
• Because ubiquitin includes seven lysines, it is possible to form ubiquitin
chains on the target protein. This might need the use of the same or a
different E3 and the assistance of an E4 enzyme.
• Deubiquitinases (DUB) are specialized enzymes that may shorten or even
eliminate all ubiquitins from a target.

Although Aβ is not directly ubiquitinated, this route involves other proteins

implicated in its destruction. NFTs are likewise ubiquitinated to a high degree.
Polyubiquitinated proteins accumulate as a result of UPS malfunction, as shown
in various neurodegenerative illnesses such as Alzheimer's disease, Parkinson's
disease, and Huntington's disease (HD). In AD, it appears that the ubiquitin-
related pathways are involved in the development of abnormal neuritic
processes and NFTs rather than Aβ accumulation.

Figure 6

10
Lysosomal Processing: Most external and cell surface proteins can be
internalized in lysosomes by receptor-mediated endocytosis. Acid proteases
(such as cathepsins B, H, L, and D) and acid hydrolases can be found in these
organelles (such as phosphatases, nucleases, proteases, and glycosidases).
Material targeted for breakdown is initially encased in phagophores, which are
subsequently wrapped into double-membrane vesicles termed autophagosomes,
which can then merge with late endosomes to form an amphisome. After being
enveloped in autophagic vacuoles that combine with lysosomes for elimination,
certain cytosolic proteins are destroyed.

Other Enzymes

Protease: Many proteases can break down amyloid-beta (both Abeta42 and
Abeta40). The insulin-degrading enzyme (IDE) and neprilysin have received
the greatest attention. The cytosol, intracellular membranes, and cell surface all
contain zinc metalloproteinase IDE. Neurons secrete it, and it's also present in
the CSF. As a result, it may break down both intracellular and extracellular Aβ.
Only soluble, monomeric Aβ is degraded by IDE. The cleavage products aren't
neurotoxic, and they don't tend to build up in plaques. Because Neprilysin is an
axonal and synaptic membraneanchored protein with its catalytic site towards
the cell outside, it is predominantly responsible for the breakdown of
extracellular Aβ42. It can break down both monomeric and oligomeric Aβ.

Microglia: Brain macrophages are known as microglia. They absorb soluble

Amyloid-beta by macropinocytosis and potentially through Amyloid-beta
binding to the low-density lipoprotein receptor-related protein (LRP). Aβ
fibrillar forms bind to the CD36 receptor produced by microglia and connect
with their cell surface. The microglial response to Aβ is mediated by CD36, a
key pattern recognition receptor, which triggers an intracellular signaling
cascade that promotes phagocytosis. Microglia ablation in mice increased
soluble Abeta40 and Abeta42 but did not affect the quantity or size of Amyloid-
beta plaques. This would back with the theory that microglia aren't very good at
digesting fibrillar Aβ. Others, on the other hand, have discovered that when
microglia are activated, such as by cerebral ischemia or immunization with
Amyloid-beta specific antibodies, they may perform a variety of functions.

The M13 family of zinc-metalloproteases includes the endothelin-converting

enzyme, which converts inactive large endothelin to its active mature version
and controls blood flow. Big endothelin-1 and -2, powerful vasoconstrictor
peptides generated by vascular endothelial cells, are the major substrates for
11
ECE. ECE-1 is particularly intriguing since its isoforms are found in diverse
places on the cell surface and within distinct intracellular compartments,
including endosomes. ECE-2 and its isoforms are related enzymes with
comparable activity, but their distribution appears to be solely intracellular,
including endosomes, and the significance of their variably spliced isoforms is
unknown. ECE-1 comes in four different human isoforms (735–770 amino
acids), all of which are encoded by a single gene on chromosome 1. (1p36).
Along with a common transmembrane region, each isoform possesses a distinct
N-terminal cytoplasmic domain that defines its subcellular distribution. ECE
preferentially cleaves hydrophobic substrates on the N-terminal side, which
corresponds to the A peptide residues Leu17, Val18, and Phe20 of the Aβ. The
structures of Neprilysin (NEP) and Endothelin Converting Enzyme are similar.
NEP is a monomer, whereas ECE-1 is a dimer with a disulfide bond. ECE-1 is
less susceptible to thiorphan than NEP, although it is blocked by
phosphoramidon. The Aβ degrading enzyme.ECE-1 is the most well-studied. At
acid pH, Aβ is cleaved with a high predilection for Aβ40 and Aβ42.

Figure 7- Amyloid-β production And Degradation

12
The amyloid precursor protein is made in the endoplasmic reticulum (ER) and
transferred to the Golgi body, where it is packed into a vesicle (orange circle) to
be delivered to the cell surface (Step 1APP that isn't processed by α-secretase in
the secretory route is internalized into endosomes (large blue circle), acidic
compartments (Step 2 & 3). In the endosome, BACE1 cleaves APP to produce
the C-terminal fragment (CTF), which is subsequently converted into amyloid
(Aβ) by γ-secretase (Step 4). ECE and unknown proteases digest a considerable
amount of Aβ produced in this compartment in the neuron (Step 5). Aβ may
evade this route and be delivered to the lysosome, where it will be degraded
(Step 6). Aβ containing recycling vesicles (Small Blue Circle) can be recycled
to the cell surface through the Golgi Apparatus (Steps 7& 8) or straight from the
endosome to the cell surface (Step 9). The ubiquitin-proteasome system (UPS)
may release Aβ from recycling vesicles (Step 10) or degrade it at the cell
surface via other recognized routes such as NEP, IDE, MMP-9, or an
undiscovered mechanism. The Aβ that hasn't been degraded can be emptied into
the cerebrospinal fluid (CSF) or removed through the lymphatic or vascular
circulation. Failure of all these redundant turnover mechanisms will lead to
accumulation and aggregation of amyloid-β[15]

Clearance of Amyloid-β: Extracellular clearance of Aβ42 and Aβ40 is also

possible. It can either be cleared from the ISF to the circulation by crossing the
blood-brain barrier, or it can be transferred from the ISF to the CSF and cleared
there. Aβ can also be delivered to the lymphatic system via the ISF or CSF
(SPIES et al., 2012)

Current Strategy for Delivery of Alzheimer’s Drugs Targeting β-Amyloid-

There are five FDA-approved medications including tacrine, donepezil,
rivastigmine, galantamine, and memantine (NMDA Receptor Antagonist) for
enhancing memory and cognitive function in Alzheimer's patients. These
medications work by increasing the quantity of neurotransmitters in the brain,
which has been demonstrated to enhance cognition in mild to moderate
Alzheimer's disease patients for six months. Not only are the therapy options
non-specific to Alzheimer's disease, but there is also no sensitive and specific
diagnostic test for the disease. Two factors hamper research First, the cause of
Alzheimer’s disease is not fully understood. Second, the blood brain barrier
restricts drug efficacy. The role of the blood-brain barrier (BBB) must be
addressed in the treatment of Alzheimer's disease[16]

13
 Figure 8

Approach To Target β-Amyloid

• One method of preventing aggregation is to use molecules/ligands that
directly bind to amyloid and modify or inhibit its aggregation. PEG
nanoparticles, lipid-based nanoparticles including phosphatidic acid and
cardiolipin, small compounds (such as curcumin and melatonin),
monoclonal antibodies (MAbs) directed against Aβ, and other peptidic
aggregation inhibitors are among them.
• Active immunotherapy, or Aβ vaccines, is another strategy that has been
shown to reduce amyloid accumulation in the brain in animal models.
However, safety concerns have restricted the use of active amyloid
vaccinations.
• A third strategy is to stop aggregation at the source by focusing on its
precursor, either APP or the enzymes that cleave it. The effects of APP
and secretase inhibition are unknown, but they are thought to have
hazardous implications for downstream pathways since they are involved
in a variety of brain functions.

Blood-Brain Barrier: For an adult person, the BBB has an average surface
area of 12–18 m2. The BBB is absent in just a few places, including the
circumventricular organs (CVO). However, blood-borne chemicals cannot
penetrate the BBB-protected area due to a sophisticated mechanism encircling
CVO. Transportation of nutrients and important molecules over the BBB, as
14
well as the removal of neurotoxins such as Aβ-peptides from the brain, is
reduced by capillary degeneration. The BBB is a capillary wall made up mostly
of brain endothelial cells and their basement membrane, with cell-cell junctions
to maintain the brain microvasculature's integrity. Cell-cell adhesion can be
categorized into adherens junctions and tight junctions. The tight junctions
preclude the paracellular transport of movement of most of the molecules and
ions. The BBB includes several highly selective pathways for nutrition delivery
into the brain. here are six basic transport mechanisms by which solute
molecules can cross the BBB. The first is passive paracellular diffusion (PPD),
which is the transfer of chemicals across epithelial cells' intercellular spaces.
Due to the existence of tight junctions, this route is almost non-existent in the
healthy BBB. The second is passive transcellular diffusion (PTD), molecules
pass through the bilayer cell membrane into the intracellular space. The third is
solute carrier proteins (SCP), a form of carriermediated endocytosis, in which
solute molecules bind to specific membrane protein carriers, also from high to
low concentration. Fourth is simple diffusion through a receptor-mediated
transcytosis (RMT), specific binding of a serum protein to its transcytosis
receptor on the apical side induces the formation of the transcytosis vesicle. The
next is adsorptive-mediated transcytosis (AMT), which interacts with
negatively charged proteins on the endothelial cell surface to allow for drug
administration across the BBB. Tight junction modulation (TJM) is the last
mechanism, which does not exist in the healthy BBB and whose mechanism of
action is unknown.

The medications now utilized to treat neurological illnesses are tiny and
lipophilic, and they enter the CNS through PTD in the case of Alzheimer's
disease treatment. Temporarily disrupting the tight connections between
endothelial cells, allowing for transitory permeability to systemic drug
molecules, is an alternate way for physically bypassing the BBB. RMT has been
intensively researched for delivering antibody-drug conjugates, liposomes, and
nanoparticles to the CNS across the BBB. Small-molecule medications might
also be engineered to traverse the BBB via endogenous carrier-mediated
transport mechanisms found in the brain capillary endothelium. Large molecule
medications including recombinant proteins, peptides, and antisense
radiopharmaceuticals will be carried over the BBB using molecular trojan horse
technology, which targets the endogenous receptor-mediated transport system
(RMT) expressed inside the brain capillary endothelium[16]

15
Figure 9: PPD (Passive Paracellular Diffusion), PTS (Passive Transcellular
Diffusion), SCP (Solute Carrier Protein Influx), RMT (Receptor-Mediated
Transcytosis), AMT (Adsorptive Mediated Transcytosis), and TJM (Tight
Junction Modulation) are all terms for the transport of solutes from the blood to
the brain across the blood-brain barrier[16]

Syn B Vectors: CPPs (cationic Proteins or Cell-Penetrating Peptides) are short

amphipathic or cationic peptides with 10 to 27 amino acid residues that
penetrate cellsCertain CPPs can pass cell membranes without the use of a
receptor by forming strong non-specific electrostatic interactions with the
negatively charged cell membrane. Syn-B vectors, for example, traverse the
BBB via adsorptive-mediated endocytosis. Syn-B vectors are peptides
generated from the natural antimicrobial peptide protegrin 1 (PG-1) found in
mammals, which have a strong affinity for biological membranes. PG-1 is an
18-amino acid peptide isolated from porcine leukocytes with an antiparallel
beta-sheet structure stabilized by two disulfide bridges[17], [18]. These vectors
can pass through the membrane without causing it to be disrupted. There are no
stereospecific receptors involved in the absorption of these vectors in the brain.
These peptide families have been employed to deliver poorly brain-penetrating
medicines to the brain. L-SynB1, L-SynB3, and-SynB3 greatly boost
16
doxorubicin absorption in the brain by 30-fold. SynB1 also improves
benzylpenicillin (BPc) absorption in the brain without jeopardizing the BBB's
integrity[19]

TAT-Derived Peptides: TAT-derived peptides, which are another kind of CPP,

have also been widely explored for drug delivery. They're made from the human
immunodeficiency virus's transcription activating factor (HIV-1). TAT protein is
an 86-amino-acid protein with a 48– 60amino-acid functional domain for
translocation [20] The cell-penetrating ability of TAT is highly related to its
arginine residues. Substituted arginine residues in TAT resulted in an obvious
decrease in penetrability TAT does not exhibit selectivity in molecular
transduction, but its ability to traverse the BBB has made it the most extensively
used CPP for delivering proteins and nanoparticles to the brain. In vitro, the
hexamer [A1-6A2VTAT(D)] formed by connecting TAT peptides with a natural
version of Aβ containing the A2V substitution substantially prevented
oligomerization, amyloid fibril formation, and Aβ-dependent neurotoxicity,
according to research. After short-term therapy, it also reduced Aβ aggregation
and cerebral amyloid accumulation in Vivo. Even though [A1-6A2VTAT(D)]
reduced cognitive decline following long-term therapy, there was an increase in
amyloid load. It might be because of TAT's inherent potential to cause Aβ
deposition, tau phosphorylation, and consequent neuronal death in AD[21].
Recent research has found that a unique fusion peptide made by combining the
brain-derived neurotrophic factor (BDNF) with TAT may effectively target
numerous biochemical pathways in the brain. BDNF is unable to penetrate the
BBB due to its enormous molecular weight. The benefits of TAT's penetrating
ability and BDNF's selectivity were coupled in this technique. In the therapy of
CNS illnesses, such as

Alzheimer's disease, double functionalization is undoubtedly a method worth

investigating. R8A25–35, a peptide made by mixing polyarginine (poly) with
A25–35, has been found to reduce Aβ accumulation and improve cognitive
functioning in APP/PS1 double transgenic mice[22]. The charge repulsion that
allows for endocytosis is due to the very hydrophilic and cationic properties of
polyarginine peptides. The mode of operation is similar to that of the TAT-
BDNF fusion peptides discussed previously.

Amyloid-Target Drug Delivery System: The hypothesis identifies Aβ plaques

as a pathological trigger for a cascade that includes neuritic injury, formation of
neurofibrillary tangles via tau protein, and cell death. The amyloidogenic
pathway produces Aβ by the action of βsecretase and γ-secretase. Aβ-binding
17
molecules have been conjugated to NPs for diagnostic therapeutic purposes that
have been developed widely. Among different NPs, liposomes and PEGPLA
NPs could be the most employed due to their reported lack of toxicity, low
immunogenicity, and full biodegradability. Liposomes conjugated with
curcumin derivatives revealed high affinity (1–5 nM) for Aβ fibrils in vitro. In
addition, the synthesis of liposomes carried phosphatidic acid (PA) or
cardiolipin (CL) that have been reported to bind Aβ with great affinity (22–60
nM) and target GM1 ganglioside.

Tau Targeted Drug Delivery System: Phosphorylation of tau and the creation
of neurofibrillary tangles both contribute to the pathophysiology of Alzheimer's
disease. Following several failures of amyloid-targeted medications, different
research has been compelled to find treating tauopathy for AD therapy, focusing
on tau aggregation prevention and improvements, such as methylene blue,
curcumin derivatives, N744, rhodamines, and aminothienopyridazines (ATPZs).
Several studies have shown that methylene blue can prevent or dissolve tau
aggregation in tauopathies in Alzheimer's disease. Curcumin, a natural
polyphenol generated by Curcuma longa plants, has been shown to have some
possibly neuroprotective qualities. Curcumin compounds were developed,
produced, and tested as dual inhibitors of A and tau aggregation by Okuda et al.
Gao et al. also disclosed neuron tau-targeting biomimetic NPs for curcumin
administration that would slow the course of Alzheimer's disease by preventing
tau aggregation[23]

Several tau-targeted nanomaterials, such as produced folic acid-functionalized

gold nanoparticles (FA-AuNPs) and Gold-Fe3O4core–shell NPs (AuFeNPs),
has been created to deliver medications for the treatment of Alzheimer's disease.
Shweta et al. [ found that protein-capped metal NPs could inhibit tau
aggregation in AD. The development of tau pathology provides a complex
multifactorial process, presenting multiple points where therapeutic intervention
is possible.

Mitochondrial Therapy for Alzheimer's Disease with Targeted

Nanoparticles: Mitochondria are organelles found in eukaryotic cells that are
involved in oxidative metabolism. Because of the loss of mitochondrial
biogenesis and mtDNA mutations, reactive oxygen species (ROS)-induced
neuronal mitochondrial dysfunction plays a significant role in sporadic AD
pathogenesis. Following the failures of phase III clinical trials on traditional A-
targeted treatment, brain mitochondria have lately been recommended as a
viable therapeutic target for Alzheimer's disease. Mitochondrial malfunction,
18
which is linked to synaptic abnormalities and neuronal degeneration, is one of
the early occurrences in Alzheimer's disease, and Aβ accumulates in the
mitochondria of AD patients, according to post mortem brain investigations
Kwon et al. reported that mitochondrial targeting of ceria NP (Nanoparticles)
might be used to treat Alzheimer's disease. The findings revealed that
mitochondrial-localized ceria nanoparticles successfully inhibited neuronal
death and restored neuronal viability in AD mice. NPs cannot penetrate the
BBB and must be injected into the ipsilateral hippocampus stereotactic area.
Furthermore, the NPs are made from inorganic materials, which have various
drawbacks, including difficult biodegradation in vivo, which limits the practical
applicability of
the suggested NPs for AD treatment. To overcome these limitations, a new
biomimetic for functional antioxidant delivery to neuronal mitochondria was
developed by loading antioxidants into red blood cell (RBC) membrane-coated
nanostructured lipid carriers (NLC) bearing rabies virus glycoprotein (RVG29)
and tri-Phenyl phosphine cation (TPP) molecules conjugated to the RBC
membrane surface (RVG/TPP NPs@RBCm), which were able to target neuron
cells and further localized in the Mitochondria[24].

ROS-induced mitochondrial dysfunction in Alzheimer's disease is a possible

therapeutic target. In vitro and in vivo studies have shown that the
mitochondrial respiratory chain molecule CoQ10 can reduce excessive ROS
generation in AD patients in both in vitro and in vivo investigations involving
target mitochondria, the benzoquinone idebenone was shown to prevent Aβ-
induced neurotoxicity. In clinical investigations of mild cognitive impairment
and Alzheimer's disease, other antioxidants such as lipoic acid, vitamin C, E,
and glutathione (GSH) were discovered.

Potential Nanotechnology Therapy for Alzheimer’s Disease: More research

is now looking at the prospect of employing nanoparticles (NPs), which are
ultrasmall objects that may be coated with medicines, to deliver targeted
therapies for a variety of ailments while avoiding hazardous side effects.
Innovative drug development techniques are required to overcome CNS
medicines' inability to permeate the BBB. Polymer [25], solid lipid carriers,
lipo-carriers, lipoprotein-based nanoparticles, curcumin-loaded nanoparticles,
metalbased carriers, nanoparticle conjugates, cubosomes, intranasal
administration of nanoparticles, and inorganic nanoparticles are some of the
nanotechnology-based techniques.

19
Polymer-Based Nanoparticles (NPs): Polymeric NPs are the most appealing
among NPs because of their biodegradability, biocompatibility, extended shelf
life, and storage stability, which might enable a regulated and sustained load
release. The most often utilized polysaccharide as a form of NPs for
pharmaceutical applications is lactic-co-glycolic acid (PLGA), whereas
synthetic polysaccharides include poly (lactic acid) (PLA), poly (glycolic acid)
(PGA), and poly (D, LLactic-co-Glycolic acid). (PLGA). Furthermore,
triphenylphosphonium (TPP) has been combined with PLGA-block-PEG to
create PLGA-b-PEG-TPP NPs for the treatment of Alzheimer's disease.
Biodegradable PLGA NPs, in particular, have been shown to have a role in
neuroprotective effects aimed at AD therapy, and CoQ10-loaded PLGA NPs
have been generated to protect against A cytotoxicity and restore memory in an
AD mouse model. Depending on the technique of synthesis, polymer NPs can
take the shape of nanocapsules or nanospheres. In addition, in vitro, and in vivo
investigations have shown that particular ligands and antibodies coupled into
solid lipid NPs inhibit A aggregation. Furthermore, Zhang et al. created a
dualfunction NP drug delivery system by conjugating PEGylated polylactic acid
(PLA) polymer with TGN and QSH (two targeting peptides), which precisely
target BBB ligands and Aβ1–42, respectively. NPs are non-human primates.

20
Figure 10: Alzheimer's disease therapy using nanotechnology-based medication
delivery systems. T.T. Nguyen and colleague.
Inorganic Nanoparticles: By regulating size, shape, surface, and domain
contacts, inorganic NPs seem nontoxic, hydrophilic, biocompatible, and very
stable under physiological conditions.

Inorganic NPs have inherent surface plasmon resonance and electrical

characteristics of metal NPs (e.g., gold NPs, silver NPs, size range 2–100 nm),
magnetic properties (iron oxides NPs), and optical properties (as gold NPs,
silver NPs, size range 2–100 nm) (rare-earth-doped NPs). Biopolymers,
chitosan, gelatin, polymers, and metal-NPs are some of the biocompatible NPs
that have been developed and found to be useful for the treatment of
Alzheimer's disease [25]. Several inorganic NPs have been described to
eliminate Aβ aggregation and suppress Aβ fibrillation, including monomers
[26], gold carriers, a magnetic core [28], carbon-based NPs, and graphene oxide
sheets. In vitro, graphene oxide (GO)/Au-NPs were the most effective NPs for
disrupting Aβ aggregation and lowering cytotoxicity, whereas nano-Metallo-
21
supramolecular complexes could block Aβ-induced heme production and iron
absorption by PC12 cells. Quantum dots (QDs) were coupled with
dihydrolipoic acid (DHLA), which is a possible therapy for Alzheimer's disease.
Furthermore, molybdenum disulfide (MoS2) NPs have recently been produced
and employed in vivo to inhibit Aβ aggregation and disrupt Aβ fibrils. Ceric
oxide (CeO2) NPs have recently been proposed as recyclable ROS scavengers
due to their ability to switch between Ce3+ and Ce4+ oxidation states. CeO2-
NPs have been developed and demonstrated to be a potential therapeutic
candidate in AD treatment that targets mitochondrial oxidative-stress-induced
damage. In another study, titanium oxide (TiO2) NPs were shown to reduce
glutathione peroxidase, catalase, and superoxide dismutase activities in a mouse
model of neurotoxicity, suggesting that they might be used as an anti-drug.
Alzheimer's.

Nanoparticles: Liposomes were developed in the 1960s and are essential

because of their unique qualities, such as being a biocompatible, highly flexible
drug delivery system that can transport a wide range of bioactive chemicals on
both the inside and outside of the particle [28, 29]. Multi-functional liposomes
containing a curcumin derivative and a BBB transport mediator (anti-transferrin
antibody (TrF)) have been developed recently, which had high affinities for
amyloid deposits with therapeutic potential. Balducci et al. conducted a key
study to look at the ability of multifunctional liposomes to target Aβ [27]. These
liposomes were bi-functionalized with mApoE to enhance crossing of the BBB,
and with phosphatidic acid (PA), which is a highaffinity ligand for Aβ. Their
results from in vivo studies show a reduction in amyloid plaque load only with
mApoE-PA-LIP, which is useful in the treatment of AD.
Lipid/ Lipoprotein Based NPs: Lipoprotein-based NPs are employed for
therapeutic applications and are known to have a high affinity for Aβ, allowing
it to be degraded more easily. An apolipoprotein E3–reconstituted high-density
lipoprotein (ApoE3–rHDL) NP system was designed and obtained to eliminate
Aβ aggregation, implying that ApoE3–rHDL might be used therapeutically in
the treatment of Alzheimer's disease. In addition, Muntimadugu et al. (2016)
developed the intranasal delivery of tarenflurbil (TFB) to the brain using
TFBloaded poly(lactideco-glycolide) NPs (TFB-NPs) or solid lipid NPs (TFB-
SLNs) that were able to the modulation of the enzyme γ-secretase responsible
for the cleavage of APP, thereby causing a reduction in Aβ.

However, the safety of nanotherapeutic techniques has to be further

investigated, particularly via further in vivo research. Before moving on with
clinical trials, more research on the pharmacokinetic and pharmacodynamic
22
properties of the released medicines is needed. Many investigations are still in
the animal model stage, or perhaps merely in vitro. This paper attempted to
review recent nanomedicine breakthroughs in the treatment of Alzheimer's
disease. However, more powerful, non-toxic nanomedicine formulations are
needed to effectively address the problems posed by CNS illnesses such as
Alzheimer's disease. The unique properties of these nanomaterials, as
highlighted here, open up an exciting new range of possibilities for both
existing compounds and novel formulations, and they are certain to provide an
alternative way to Open New and Exciting Avenues for Therapeutic
Intervention AD drug development in the years to come. antibody (OX26 mAb)
acted as carriers that gained to transport the bioactive extract to the in-vitro
model of the human BBB[28], offering new hope for AD treatment.

Concluding Remark and Future Perspective

Exploring therapeutic strategies for AD is one of the biggest challenges in the
field of CNS drug development. Also, the existence of BBB prevents
therapeutic agents from entering the CNS, which is also an insurmountable
obstacle for AD treatment. To date, the causative factors of AD are not fully
understood while AD seems to start during middle age and progresses silently
for many years, as well as clinical symptoms of dementia do not occur until the
final stage of the disease. The main focus for drug discovery efforts has been to
interfere with the amyloid pathway, which includes preventing production and
aggregation or increasing the elimination of Aβ peptides. No anti-amyloid drug
for the treatment of AD has yet reached the market. AD may be such a
heterogeneous disease that a multimodal approach is necessary to stop the
disease’s progress. Through the different AD pathogenesis hypotheses, current
nanotherapeutic strategies in AD include Aβ targeting, metal ions binding,
cholinesterase inhibition, neuroprotection, and estrogen replacement therapy.
These nanocarriers can be functionalized by the addition of the active drug
compound, as well as targeting molecules. The available pharmacologic studies
for mainly on the development of disease-modifying drugs to slow or prevent
AD development. Hence, a promising approach may come from NPs with a
multi-drugs payload or combined within a single delivery platform that allows
reaching different tasks in one shot. Recent studies have revealed that NPs can
effectively cross the BBB and exert inhibitory effects that can enhance targeting
and efficacy at specific pH values and temperatures[29]. In addition, surface
modification on the nanocarriers also enable brain-targeting or even Aβ
targeting drug delivery for enhancing therapeutic efficacy and reducing side
effect. mitochondria-targeted therapeutic AD interventions that could be
translated from in vitro and in vivo studies to human clinical trials. The
23
therapeutic potential of cerium dioxide, or ceria, NPs lies in the fact that the
surface cerium atoms can exist in either +3 or +4 oxidation states and act as
facilitators of redox reactions [30]. Since Aβ deposition, tau neurofibrillary
tangles, and neuroinflammation are involved in the pathophysiology of AD in
the disease process, targeting these forms of the molecules with NP-
functionalized monoclonal antibodies might lead to greater success in clinical
studies.

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