Du et al.

Translational Neurodegeneration (2018) 7:2

DOI 10.1186/s40035-018-0107-y

REVIEW Open Access

Alzheimer’s disease hypothesis and related

therapies
Xiaoguang Du1, Xinyi Wang1 and Meiyu Geng2*

Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause for dementia.
There are many hypotheses about AD, including abnormal deposit of amyloid β (Aβ) protein in the extracellular
spaces of neurons, formation of twisted fibers of tau proteins inside neurons, cholinergic neuron damage,
inflammation, oxidative stress, etc., and many anti-AD drugs based on these hypotheses have been developed. In
this review, we will discuss the existing and emerging hypothesis and related therapies.
Keywords: Alzheimer’s disease - complicated disease - anti-AD drugs, Hypothesis about AD

Background Current hypothesis about AD and anti-AD drug

Alzheimer’s disease (AD) is a progressive neurodegener- development
ative disorder, which is the most common cause for AD is a complicated disease involving many factors. Due
dementia and imposes immense suffering on patients to the complexity of human brains, the lack of reason-
and their families. According to the World Alzheimer able animal models and research tools, the detailed
Report 2016, there are currently about 46.8 million pathogenesis of AD is still unclear so far. Many hypoth-
people suffering with AD worldwide. The ageing of eses about AD have been developed, including amyloid
world population will further compound this problem β (Aβ), Tau, cholinergic neuron damage and oxidative
and lead to a steep increase in the number of AD stress, inflammation, etc. Thus, many efforts have been
patients. The numbers of AD patients are expected to done to develop anti-AD drugs based on these hypotheses.
double nearly every 20 years, and thereby the population
of AD will reach 74.7 million in 2030 and 131.5 million
in 2050 [1]. AD has become the third major cause of dis- Aβ cascade hypothesis
ability and death for the elderly, only after cardiovascular Extracellular deposits of Aβ peptides as senile plaques,
and cerebrovascular diseases and malignant tumors. intraneuronal neurofibrillary tangles (NFTs), and large-
However, only five drugs have been approved by the scale neuronal loss were the main pathological features
FDA to treat AD over the past hundred years since the of AD. Thus, Aβ peptides have long been viewed as a
first AD patient was diagnosed. Not only that, these potential target for AD which dominated new drug re-
approved drugs including cholinesterase inhibitors, N- search during the past twenty years [2]. The most direct
methyl-D-aspartate (NMDA) receptor antagonist or strategy in anti-Aβ therapy is to reduce Aβ production
their combination usually provide temporary and incom- by targeting β- and γ-secretase [3]. Safety issues are the
plete symptomatic relief accompanied with severe side overriding problem. For targeting γ-secretase, undesir-
effects. The marginal benefits were unable to slow the able side effects are inevitable due to its physiological
progression of AD. Thus, developing drugs for more substrates, eg. the Notch signaling protein [4–7], which
effective AD treatment is in urgent need. is essential in normal biological process. Similarily, tar-
geting β-secretase is also challenged for the side effects
such as blindness and the large catalytic pocket [8].
* Correspondence: mygeng@simm.ac.cn More importantly, in sporadic AD cases, the majority of
2
State Key Laboratory of Drug Research, Shanghai Institute of Materia AD patients do not necessarily have over-producted
Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai
201203, People’s Republic of China amyloid precursor protein. Besides, Aβ isoforms
Full list of author information is available at the end of the article could also serve as endogenous positive regulators
© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Du et al. Translational Neurodegeneration (2018) 7:2 Page 2 of 7

for neurotransmitter release at hippocampal synapses Tau hypothesis

[9]. Thus, inhibiting Aβ production may encounter Neurofibrillary tangles, another intracellular hallmark of
many challenges. AD, are composed of tau. Tau is a microtubule-
Aβ clearance by immunotherapy is the alternative associated protein working as scaffolding proteins that
choice. For active Aβ-immunotherapy, although the first are enriched in axons. In pathological conditions, tau
active AD vaccine (AN1792) developed by ELAN aggregation will impair axons of neurons and thus cause
showed some beneficial effects such as less cognitive de- neurodegeneration. After numerous failures of Aβ-
cline, it was suspended owing to serious side effect, or targeting drugs for AD, more interests are turning to
meningoencephalitis [10–12]. Also, the passive immuno- explore the therapeutic potential of targeting tau,
therapy did not do much better than active immuno- particularly as studies of biomarkers suggest that tau
therapy. Several antibodies targeting Aβ have failed in pathology is more closely linked to the progression of
clinical trials, including bapineuzumab (Pfizer/Johnson AD [38].
& Johnson) [13, 14], Crenezumab (Genentech) [15, 16], Tau undergoes many modifications, including phos-
solanezumab (Eli Lilly) [16–18] and ponezumab phorylation, arginine monomethylation, lysine acetyl-
(Johnson & Johnson /Pfizer) [19–21]. In addition, ation, lysine monomethylation, lysine dimethylation,
although passive immunotherapy could overcome some lysine ubiquitylation and serine.
problems of active immunotherapy, there were still O-linked N-acetylglucosamine (O-GlcNAc) modifica-
inevitable side effects such as amyloid-related imaging tion [39]. Under pathological conditions, increasing of
abnormalities [22]. Likewise, the small molecule Aβ tau hyperphosphorylation will render the protein
binder scyllo-inositol [23] and tramiprosate [24–26] also aggregation-proned, reduce its affinity for microtubules,
failed in clinical trials. These failures even cast more and thereby influence neuronal plasticity. Consequently,
doubts on the Aβ theory [27]. Actually, the strategy of strategies to target tau involve blocking of tau aggrega-
targeting only a single functional subregion of Aβ may tion, utilizing tau vaccinations, stabilizing microtubules,
partly account for these failures [27, 28]. Furthermore, manipulating kinases and phosphatases that govern tau
immunotherapy may influence the human immune sys- modifications. However, most of these efforts have failed
tem, which might cause beneficial or detrimental conse- in clinical trials. For Tau aggregation blockers, TRx0237
quence (such as side effects). However, every cloud has a failed to show treatment benefits in phase III trials [40].
silver lining. A phase Ib trial of aducanumab (Biogen) As for vaccinations, tau-targeted active vaccines (ACI35
showed a positive correlation between brain Aβ levels and AADvac-1) and passive vaccines (RG6100 and
and disease exacerbation as measured by Clinical ABBv-8E12) are currently in phase I and II clinical trials
Dementia Rating [29–31]. Even the failed phase III [41, 42]. Intravenous immunoglobulin (IVIG), the only
EXPEDITION3 trial of solanezumab (Eli Lilly) still passive vaccine in phase III clinical trials, failed to meet
demonstrated better performance in Clinical Dementia the primary end points in patients with mild-to-
Rating Sum of Boxes and beneficial impacts on Mini- moderate AD [42]. Other tau-targeting strategies for
Mental State Examination and Activities of Daily Living AD, including stabilizing microtubules and manipulating
[17, 18, 32, 33]. Thus, despite all kinds of problems, kinases and phosphatases, have just been tested in pre-
immunotherapy may still be the better approach to clinical studies.
modify the extent of neurodegeneration in AD cur- In general, tau-targeting therapies remain challenging
rently [34]. because of incomplete understanding of AD, lack of
In fact, the original amyloid cascade hypothesis was robust and sensitive biomarkers for diagnosis and
that “Aβ is the causative agent in Alzheimer’s Disease response-monitoring, and the obstruction of blood-brain
pathology, and that neurofibrillary tangles, cell loss, vas- barrier.
cular damage, and dementia follow as a direct result of
this deposition” [35]. After decades of research, although Inflammation hypothesis
the bulk of data still supports a role for Aβ as the pri- Reactive gliosis and neuroinflammation are hallmarks of
mary initiator of the complex pathogenic cascade in AD, AD. Microglia-related pathways were considered to be
more and more evidences indicate that Aβ acts as a trig- central to AD risk and pathogenesis, as supported by
ger in the early disease process and appears to be neces- emerging genetic and transcriptomic studies [43–47].
sary but not sufficient in the late stage of AD [36]. Increasing evidence demonstrate that microglia emerges
Especially, recent rapid progresses in understanding as central players in AD. In very early stage, microglia,
on toxic amyloid assembly and Aβ metabolism TREM2 and complement system are responsible for
associated systemic abnormalities will provide fresh synaptic pruning [48, 49]. The processes of activity-
impetus and new opportunities for this interesting dependent and long-term synaptic plasticity are the com-
approach [37]. mon and fundamental cellular underpinning of learning
Du et al. Translational Neurodegeneration (2018) 7:2 Page 3 of 7

and memory which may manifest as influence on long can also induce oxidative stress [67–73]. Thus, the
term potential [50]. Following that, reactive microglia and treatment with anti-oxidant compounds would provide
astrocytes will surround amyloid plaques and secrete protection against oxidative stress and Aβ toxicity in
numerous pro-inflammatory cytokines. These events are theory. However, oxidative stress is only a single feature
regarded as an early, prime mover in AD evolution. How- of AD, so antioxidant strategy was challenged for its
ever, non-steroid anti-inflammatory drugs (NSAIDs) did potency to stop the progression of AD and thus it is
not show enough benefits in clinic. This is because that proposed as a portion of combination therapy [74, 75].
the relationship between innate immunity and AD patho-
genesis is complex, and the immune response can be ei- Glucose hypometabolism
ther deleterious or beneficial depending on the context Glucose hypometabolism is the early pathogenic event
[47, 51, 52]. However, the new observations that PD-1 im- in the prodromal phase of AD, and associated with cog-
mune checkpoint blockade reduces the pathology of AD nitive and functional decline. Early therapeutic interven-
and improves memory in mouse models of AD [53–55] tion before the irreversible degeneration has become a
give us a direction of future researches. consensus in AD treatment. Thus, alleviation of glucose
The recent advances in our understanding of the hypometabolism was emerged as an attractive strategy of
mechanism underlying microglia dysfunction in pruning, AD treatment. However, most of these therapeutic strat-
regulating plasticity, and neurogenesis are opening up egies are targeting mitochondria and bioenergetics,
possibilities for new opportunities of AD therapeutic which have shown promise at the preclinical stage but
interventions and diagnosis [56, 57]. Targeting these without success in clinical trials [76, 77]. Although no
aberrant microglial functions and thereby returning strategies are available to alleviate glucose hypometabo-
homeostasis may yield novel paradigms for AD therap- lism in clinical, glucose metabolism brain imaging such
ies. However, given the complexity and diverse functions as 18FDG-PET (Positron emision tomography with 2-
of microglia in health and disease, there is a crucial need deoxy-2-fluorine-18-fluoro-D-glucose) has become a
for new biomarkers reflecting the function of specific valuable indicator for diagnosis of neurodegenerative
microglias [52, 58]. diseases that cause dementia, including AD [78].
Up to now, there’re no effective treatments for
Cholinergic and oxidative stress hypothesis changing the course of AD. Confronting these difficul-
Acetylcholine (ACh) is an important neurotransmitter ties, we should get deeper understandings about these
used by cholinergic neurons, which has been involved in hypotheses, and meanwhile we should renovate our
critical physiological processes, such as attention, learn- knowledge about AD and develop new hypothesis.
ing, memory, stress response, wakefulness and sleep, and
sensory information [59–63]. Cholinergic neurons dam- New pathway to AD
age was considered to be a critical pathological change AD is conventionally regarded as a central nervous sys-
that correlated with cognitive impairment in AD. Thus, tem (CNS) disorder. However, increasing experimental,
cholinergic hypothesis was firstly tested with cholinester- epidemiological and clinical evidences have suggested
ase inhibitors in AD treatment. Tacrine, a cholinesterase that manifestations of AD extend beyond the brain.
inhibitor, was the first anti-AD drug available in clinic Most notably, research over the past few years reveals
[64–66] although it was withdrawn from the market in that the gut microbiome (GMB) has a profound impact
2012 due to severe side effects. Although inhibiting on the formation of the blood-brain barrier, myelination,
cholinesterase is a symptomatic relief treatment with neurogenesis, and microglia maturation [79–84]. In
marginal benefits, it is currently the most available particular, results from germ-free animals and animals
clinical treatment which gives desperate AD patients a exposed to pathogenic microbial infections, antibiotics,
glimmer of hope. For other neurotransmitter dysfunc- probiotics, or fecal microbiota transplantation showed
tion, such as Dopamine and 5-hydroxytryptamine, there that gut microbiota modulates many aspects of animal
are some studies about them, but not much as acetyl- behaviors, suggesting a role for the gut microbiota in
choline in AD. host cognition or AD-related pathogenesis [85–88]. The
Oxidative stress is considered to play an important underlying mechanisms of gut microbiota influencing
role in the pathogenesis of AD. Especially, the brain uti- brain involve the communication through immune
lizes more oxygen than other tissues and undergoes system, the endocrine system, the vague nerve, and the
mitochondrial respiration, which increases the potential bacteria-derived metabolites.
for ROS exposure. In fact, AD is highly associated with
cellular oxidative stress, including augmentation of pro- Immune pathway
tein oxidation, protein nitration, glycoloxidation and The intestinal mucosal lymphoid tissue contains 70% ~
lipid peroxidation as well as accumulation of Aβ, for Aβ 80% of the immune cells in the whole body, and is
Du et al. Translational Neurodegeneration (2018) 7:2 Page 4 of 7

considered to be the largest and most important human modulations of gut microbiota may have direct and
immune organs. It is also the first line of host defense indirect effects on AD development and progression.
against pathogens. The human gut contains a large, di-
verse and dynamic enteric microbiota, including more Endocrine pathway and the vagus nerve
than 100 trillion microorganisms from at least 1000 The gut is also the largest endocrine organ in the body.
distinct species. There’s a complex relationship between Gut microbiota can regulate secretion of many hor-
intestinal mucosal immune system and intestinal mones from intestinal endocrine cells, such as cortico-
microbiota. Thus, gut microbiota induced immuno- sterone and adrenal hormones, and thus establish the
modulation is emerging as an important pathway that information exchange between the intestines and the
influences AD [89]. brain. For example, the intestinal microbiome can affect
Gut microbiota can influence brain through immune the secretion of serotonin and regulate brain emotional
system in several ways. Firstly, intestinal microbiome activities [96, 97]; intestinal microbial metabolism can
can induce cytokines secretion, which enter the circula- also produce a variety of neurotransmitters, such as
tory system, pass through blood brain barrier, and dir- dopamine, GABA, acetylcholine and melatonin, which
ectly affect the brain function. For instance, perivascular are transmitted to central nervous system through the
macrophages and cerebral small vessel epithelial cells vagus nerve [98]. Besides transporting these signal sub-
can receive the intestinal microbiome produced IL-1 sig- stances, the vagus nerve itself plays an important role in
nal and affect central nervous system. Also, gut microbes inflammation and depression [99]. The vagus nerve can
can activate Toll-like receptors of the brain immune influence the gastrointestinal tract, orchestrate the com-
cells (such as microglia) through microbes associated plex interactions between central and peripheral neural
molecular patterns (MAMP). MAMPs can either directly control mechanisms [100]. The stimulation of vagus
bind to intestinal epithelial cells or infiltrate to the intes- nerve is able to regulate mood, and the immune system,
tine lamina propria to activate lymphocytes, promoting suggesting the therapeutic potential of vagus nerve
the release of pro-inflammatory cytokines, which further modulation to attenuate the pathophysiological changes
cause subsequent inflammation in brain. Secondly, gut and restore homeostasis [98–103].
microbes can produce metabolites such as short-chain-
fatty acids (SCFAs), gamma-aminobutyric acid (GABA) Bacteria-derived metabolites
and 5-HT precursors, which could also travel to the Generation of essential nutrients for host physiology,
brain via circulatory systems or signal through intestinal such as vitamins and other cofactors, is an important
epithelials to produce cytokines or neurotransmitters physiological function of the gut microbiota [104]. The
that activate vagus nerve. Thirdly, gut microbes can acti- metabolites of microbiome, such as SCFAs including
vate enteroendocrine cells to produce 5-HT, which affect acetate, butyrate, and propionate, are able to modulate
the brain through neuroimmune pathways. peripheral and central pathologic processes [105]. For
In addition to changing the functions of the immune example, butyrate is effective in reducing inflammation
system, such as through secretion of inflammatory fac- and pain. Once in the brain, acetate is able to alter the
tors or anti-inflammatory factors, intestinal microbiome level of the neurotransmitters glutamate, glutamine, and
can also affect the development and composition of im- GABA, as well as increases anorectic neuropeptide ex-
mune system. For example, in germ-free mice, isolated pression [106]. In addition, the gut microbiota can secrete
lymphoid follicles in gut associated lymphoid tissue are large amounts of amyloids and lipopolysaccharides, which
unable to mature, and lymphocytes that are able to se- might contribute to the modulation of signaling pathways,
crete IgA in the intestinal epithelium decreased [89–92]. the production of proinflammatory cytokines associated
For immune system in brain, the deletion of gut micro- with AD pathogenesis and Aβ deposition [107–109].
biota in germ-free mice have global influence on the cell In fact, microbiota-gut-brain axis has been established
proportions and maturation of microglia in the brain, and a disturbed gut microbiota has been incriminated in
and thus affect the properties and phenotype of micro- many neurodegenerative diseases in animal and transla-
glia, as compared to conventionally colonized controls tional models. In theory, a role for the microbiota-gut-
[93]. Similar results were obtained in antibiotic treated brain axis is highly plausible. However, the theoretical
mice. Other research also demonstrates that the number basis for the use of microbiota-directed therapies in
of T regulatory cells and T helper lymphocytes (T helper neurodegenerative disorders still needs supports from
17, Th17) are significantly reduced in the germ free high-quality clinical trials [110]. To date, only a few
mouse, indicating the regulatory effects of intestinal studies directly focused on the gut microbiota and AD
microbiome on T cell composition, while microbiome [111, 112], and studies on AD patients is particullarly
tansplant to germ free mice can modify these variations deficient. A recent research from human showed an in-
and restore normal immune function [94, 95]. All these crease in the abundance of a pro-inflammatory GMB
Du et al. Translational Neurodegeneration (2018) 7:2 Page 5 of 7

taxon and a reduction in the abundance of an anti- Author details

1
inflammatory taxon are possibly associated with a Shanghai GreenValley Pharmaceutical Co., Ltd., 421 Newton Road, Shanghai
201203, People’s Republic of China. 2State Key Laboratory of Drug Research,
peripheral inflammatory state in patients with cognitive Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu
impairment and brain amyloidosis. It is important for Chong Zhi Road, Shanghai 201203, People’s Republic of China.
the research of gut microbiota and AD. However, further
Received: 7 November 2017 Accepted: 18 January 2018
investigations are still necessary to explore the possible
causal relation between GMB-related inflammation and
amyloidosis [111]. The comprehensive understanding of References
these underlying mechanisms may provide new insights 1. Ali G-C, Guerchet M, Wu Y-T, Prince M, Prina M. Chapter 2: The global
into these novel therapeutic strategies for AD. In prevalence of dementia. In: Prince M, Guerchet M, Ali G-C, Wu Y-T, Prina M,
editors. The Global Impact of Dementia. An analysis of prevalence, incidence,
particular, based on the gut microbiota hypothesis, cost and trends. London: Alzheimer’s Disease International (ADI); 2015. p. 10–29.
Chinese traditional medicine and probiotic bacteria may 2. Cummings J, et al. Drug development in Alzheimer’s disease: the path to
play a more important role in therapy [113]. 2025. Alzheimers Res Ther. 2016;8:39.
3. Vassar R, Citron M. Abeta-generating enzymes: recent advances in beta- and
gamma-secretase research. Neuron. 2000;27(3):419–22.
Conclusions 4. van Es JH, et al. Notch/gamma-secretase inhibition turns proliferative cells in
Nowadays, new technologies are making it possible to intestinal crypts and adenomas into goblet cells. Nature. 2005;435(7044):
959–63.
get to know enough pathologic details of disease. More 5. Olry A, et al. Generation and characterization of mutant cell lines defective
importantly, scientists are beginning to treat AD as a sys- in gamma-secretase processing of notch and amyloid precursor protein. J
temic disease and they are paying more attention to the Biol Chem. 2005;280(31):28564–71.
6. Tarassishin L, et al. Processing of notch and amyloid precursor protein by
correlation between brain and other organs [47, 89, 114]. gamma-secretase is spatially distinct. Proc Natl Acad Sci U S A. 2004;101(49):
Perhaps, for complicated disease such as AD, researches 17050–5.
and therapies should be based on the principle that com- 7. Sastre M, et al. Presenilin-dependent gamma-secretase processing of beta-
amyloid precursor protein at a site corresponding to the S3 cleavage of
bined reductionism with holism, and great efforts should notch. EMBO Rep. 2001;2(9):835–41.
be made to search the fundamental laws of AD by means 8. Klaver DW, et al. Is BACE1 a suitable therapeutic target for the treatment of
of multi-scale modeling and efficient numeric assessment. Alzheimer’s disease? Current strategies and future directions. Biol Chem.
2010;391(8):849–59.
Maybe, just like Chinese traditional medicine [115], com- 9. Abramov E, et al. Amyloid-beta as a positive endogenous regulator of
bination treatments or systematic therapy will be a final release probability at hippocampal synapses. Nat Neurosci. 2009;12(12):
way out. 1567–76.
10. Gilman S, et al. Clinical effects of Abeta immunization (AN1792) in patients
with AD in AN interrupted trial. Neurology. 2005;64(9):1553–62.
Abbreviations
11. Bayer AJ, et al. Evaluation of the safety and immunogenicity of synthetic
AD: Alzheimer’s disease; Aβ: Amyloid β; CNS: Central nervous system;
Abeta42 (AN1792) in patients with AD. Neurology. 2005;64(1):94–101.
CSF1R: Colony stimulating factor 1 receptor; GABA: Gamma-aminobutyric
12. Holmes C, et al. Long-term effects of Abeta42 immunisation in Alzheimer’s
acid; IVIG: Intravenous immunoglobulin; MAMP: Microbes associated
disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet.
molecular patterns; NFTs: Neurofibrillary tangles; NMDA: N-methyl-D-
2008;372(9634):216–23.
aspartate; NSAIDs: Non-steroid anti-inflammatory drugs; O-GlcNAc: O-linked
13. Laskowitz DT, Kolls BJ. A phase 2 multiple ascending dose trial of
N-acetylglucosamine; SCFAs: Short-chain-fatty acids; Th17: T helper
bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2010;
lymphocytes 17
74(24):2026. author reply 2026-7
14. Salloway S, et al. A phase 2 multiple ascending dose trial of bapineuzumab
Acknowledgements
in mild to moderate Alzheimer disease. Neurology. 2009;73(24):2061–70.
Not applicable.
15. Ultsch M, et al. Structure of Crenezumab complex with Abeta shows loss of
beta-hairpin. Sci Rep. 2016;6:39374.
Funding 16. Bouter Y, et al. Abeta targets of the biosimilar antibodies of Bapineuzumab,
This review was supported by “Personalized Medicines-Molecular Signature Crenezumab, Solanezumab in comparison to an antibody against
based Drug Discovery and Development”, Strategic Priority Research Ntruncated Abeta in sporadic Alzheimer disease cases and mouse models.
program of Sciences, Grants No. XDA12040101. Acta Neuropathol. 2015;130(5):713–29.
17. The Lancet N. Solanezumab: too late in mild Alzheimer’ss disease? Lancet
Availability of data and materials Neurol. 2017;16(2):97.
Not applicable. 18. Gandy S, Sano M. Alzheimer disease: Solanezumab-prospects for meaningful
interventions in AD? Nat Rev Neurol. 2015;11(12):669–70.
Authors’ contributions 19. Landen JW, et al. Safety and pharmacology of a single intravenous dose of
All authors read and approved the final manuscript. XD: Forming the ponezumab in subjects with mild-to-moderate Alzheimer disease: a phase I,
concept, drafting and revising the manuscript; XW: Revising the immune randomized, placebo-controlled, double-blind, dose-escalation study.
pathway; MG: Revising and approving the manuscript. Clin Neuropharmacol. 2013;36(1):14–23.
20. Burstein AH, et al. Safety and pharmacology of ponezumab (PF-04360365)
Ethics approval and consent to participate after a single 10-minute intravenous infusion in subjects with mild to
Not relevant. moderate Alzheimer disease. Clin Neuropharmacol. 2013;36(1):8–13.
21. La Porte SL, et al. Structural basis of C-terminal beta-amyloid peptide
Consent for publication binding by the antibody ponezumab for the treatment of Alzheimer's
Not applicable. disease. J Mol Biol. 2012;421(4–5):525–36.
22. Carlson C, et al. Amyloid-related imaging abnormalities from trials of
Competing interests solanezumab for Alzheimer's disease. Alzheimers Dement (Amst). 2016;
The authors declare they have no competing interests. 2:75–85.
Du et al. Translational Neurodegeneration (2018) 7:2 Page 6 of 7

23. Salloway S, et al. A phase 2 randomized trial of ELND005, scyllo-inositol, in 53. Baruch K, et al. PD-1 immune checkpoint blockade reduces pathology and
mild to moderate Alzheimer disease. Neurology. 2011;77(13):1253–62. improves memory in mouse models of Alzheimer's disease. Nat Med.
24. Aisen PS, et al. Tramiprosate in mild-to-moderate Alzheimer's disease - a 2016;22(2):135–7.
randomized, double-blind, placebo-controlled, multi-centre study (the 54. Saresella M, et al. A potential role for the PD1/PD-L1 pathway in the
Alphase study). Arch Med Sci. 2011;7(1):102–11. neuroinflammation of Alzheimer's disease. Neurobiol Aging.
25. Greenberg SM, et al. A phase 2 study of tramiprosate for cerebral amyloid 2012;33(3):624 e11–22.
angiopathy. Alzheimer Dis Assoc Disord. 2006;20(4):269–74. 55. Saresella M, et al. PD1 negative and PD1 positive CD4+ T regulatory cells in
26. Gervais F, et al. Targeting soluble Abeta peptide with Tramiprosate for the mild cognitive impairment and Alzheimer's disease. J Alzheimers Dis.
treatment of brain amyloidosis. Neurobiol Aging. 2007;28(4):537–47. 2010;21(3):927–38.
27. Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for 56. Jevtic S, et al. The role of the immune system in Alzheimer disease: etiology
Alzheimer's disease: an appraisal for the development of therapeutics. and treatment. Ageing Res Rev. 2017;40:84–94.
Nat Rev Drug Discov. 2011;10(9):698–712. 57. McGeer PL, McGeer EG. Targeting microglia for the treatment of Alzheimer's
28. Nie Q, Du XG, Geng MY. Small molecule inhibitors of amyloid beta peptide disease. Expert Opin Ther Targets. 2015;19(4):497–506.
aggregation as a potential therapeutic strategy for Alzheimer's disease. 58. Salter MW, Stevens B. Microglia emerge as central players in brain disease.
Acta Pharmacol Sin. 2011;32(5):545–51. Nat Med. 2017;23(9):1018–27.
29. Sevigny J, et al. Addendum: the antibody aducanumab reduces Abeta 59. Hasselmo ME, Anderson BP, Bower JM. Cholinergic modulation of cortical
plaques in Alzheimer's disease. Nature. 2017;546(7659):564. associative memory function. J Neurophysiol. 1992;67(5):1230–46.
30. Sevigny J, et al. The antibody aducanumab reduces Abeta plaques in 60. Fine A, et al. Learning impairments following injection of a selective
Alzheimer's disease. Nature. 2016;537(7618):50–6. cholinergic immunotoxin, ME20.4 IgG-saporin, into the basal nucleus of
31. Patel KR. Biogen's aducanumab raises hope that Alzheimer's can be treated Meynert in monkeys. Neuroscience. 1997;81(2):331–43.
at its source. Manag Care. 2015;24(6):19. 61. Sarter M, Bruno JP. Cognitive functions of cortical acetylcholine: toward a
32. Karran E. Recent trial shows that solanezumab has disease modifying unifying hypothesis. Brain Res Brain Res Rev. 1997;23(1–2):28–46.
effects. BMJ. 2015;351:h4528. 62. Miranda MI, Bermudez-Rattoni F. Reversible inactivation of the nucleus
33. Siemers ER, et al. Phase 3 solanezumab trials: secondary outcomes in mild basalis magnocellularis induces disruption of cortical acetylcholine release
Alzheimer's disease patients. Alzheimers Dement. 2016;12(2):110–20. and acquisition, but not retrieval, of aversive memories. Proc Natl Acad Sci
34. Barrera-Ocampo A, Lopera F. Amyloid-beta immunotherapy: the hope for U S A. 1999;96(11):6478–82.
Alzheimer disease? Colomb Med (Cali). 2016;47(4):203–12. 63. Haam J, Yakel JL. Cholinergic modulation of the hippocampal region and
35. Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. memory function. J Neurochem. 2017;142(Suppl 2):111–21.
Science. 1992;256(5054):184–5. 64. Brinkman SD, Gershon S. Measurement of cholinergic drug effects on
36. Musiek ES, Holtzman DM. Three dimensions of the amyloid hypothesis: memory in Alzheimer's disease. Neurobiol Aging. 1983;4(2):139–45.
time, space and ‘wingmen’. Nat Neurosci. 2015;18(6):800–6. 65. Summers WK, et al. Oral tetrahydroaminoacridine in long-term treatment of
37. Wang J, et al. A systemic view of Alzheimer disease - insights from amyloid- senile dementia, Alzheimer type. N Engl J Med. 1986;315(20):1241–5.
beta metabolism beyond the brain. Nat Rev Neurol. 2017;13(10):612–23. 66. Summers WK, et al. Use of THA in treatment of Alzheimer-like dementia:
38. Brier MR, et al. Tau and Abeta imaging, CSF measures, and cognition in pilot study in twelve patients. Biol Psychiatry. 1981;16(2):145–53.
Alzheimer's disease. Sci Transl Med. 2016;8(338):338ra66. 67. Cheignon C, et al. Oxidative stress and the amyloid beta peptide in
39. Morris M, et al. Tau post-translational modifications in wild-type and human Alzheimer's disease. Redox Biol. 2018;14:450–64.
amyloid precursor protein transgenic mice. Nat Neurosci. 2015;18(8):1183–9. 68. Sultana R, Butterfield DA. Redox proteomics studies of in vivo amyloid beta-
40. Gauthier S, et al. Efficacy and safety of tau-aggregation inhibitor therapy in peptide animal models of Alzheimer's disease: insight into the role of
patients with mild or moderate Alzheimer's disease: a randomised, oxidative stress. Proteomics Clin Appl. 2008;2(5):685–96.
controlled, double-blind, parallel-arm, phase 3 trial. Lancet. 69. Butterfield DA, et al. Roles of amyloid beta-peptide-associated oxidative
2016;388(10062):2873–84. stress and brain protein modifications in the pathogenesis of Alzheimer's
41. Novak P, et al. Safety and immunogenicity of the tau vaccine AADvac1 in disease and mild cognitive impairment. Free Radic Biol Med.
patients with Alzheimer's disease: a randomised, double-blind, placebo- 2007;43(5):658–77.
controlled, phase 1 trial. Lancet Neurol. 2017;16(2):123–34. 70. Mohmmad Abdul H, et al. Mutations in amyloid precursor protein and
42. Li C, Gotz J. Tau-based therapies in neurodegeneration: opportunities and presenilin-1 genes increase the basal oxidative stress in murine neuronal
challenges. Nat Rev Drug Discov. 2017; cells and lead to increased sensitivity to oxidative stress mediated by
43. Zhang B, et al. Integrated systems approach identifies genetic nodes and amyloid beta-peptide (1-42), HO and kainic acid: implications for
networks in late-onset Alzheimer's disease. Cell. 2013;153(3):707–20. Alzheimer's disease. J Neurochem. 2006;96(5):1322–35.
44. Guerreiro R, et al. TREM2 variants in Alzheimer's disease. N Engl J Med. 71. Gibson GL, Allsop D, Austen BM. Induction of cellular oxidative stress by the
2013;368(2):117–27. beta-amyloid peptide involved in Alzheimer's disease. Protein Pept Lett.
45. Song W, et al. Alzheimer's disease-associated TREM2 variants exhibit either 2004;11(3):257–70.
decreased or increased ligand-dependent activation. Alzheimers Dement. 72. Butterfield DA, et al. Amyloid beta-peptide and amyloid pathology are
2017;13(4):381–7. central to the oxidative stress and inflammatory cascades under which
46. Colonna M, Wang Y. TREM2 variants: new keys to decipher Alzheimer Alzheimer's disease brain exists. J Alzheimers Dis. 2002;4(3):193–201.
disease pathogenesis. Nat Rev Neurosci. 2016;17(4):201–7. 73. Butterfield DA, Lauderback CM. Lipid peroxidation and protein oxidation in
47. Bolos M, Perea JR, Avila J. Alzheimer's disease as an inflammatory disease. Alzheimer's disease brain: potential causes and consequences involving
Biomol Concepts. 2017;8(1):37–43. amyloid beta-peptide-associated free radical oxidative stress. Free Radic Biol
48. Hong S, Dissing-Olesen L, Stevens B. New insights on the role of microglia Med. 2002;32(11):1050–60.
in synaptic pruning in health and disease. Curr Opin Neurobiol. 74. Persson T, Popescu BO, Cedazo-Minguez A. Oxidative stress in Alzheimer's
2016;36:128–34. disease: why did antioxidant therapy fail? Oxidative Med Cell Longev.
49. Paolicelli RC, et al. Synaptic pruning by microglia is necessary for normal 2014;2014:427318.
brain development. Science. 2011;333(6048):1456–8. 75. Teixeira J, et al. Alzheimer's disease and antioxidant therapy: how long how
50. Bliss TV, Collingridge GL, Morris RG. Synaptic plasticity in health and disease: far? Curr Med Chem. 2013;20(24):2939–52.
introduction and overview. Philos Trans R Soc Lond Ser B Biol Sci. 76. Caldwell CC, Yao J, Brinton RD. Targeting the prodromal stage of
2014;369(1633):20130129. Alzheimer's disease: bioenergetic and mitochondrial opportunities.
51. Chen J, et al. Inhibition of AGEs/RAGE/rho/ROCK pathway suppresses non- Neurotherapeutics. 2015;12(1):66–80.
specific neuroinflammation by regulating BV2 microglial M1/M2 polarization 77. Daulatzai MA. Cerebral hypoperfusion and glucose hypometabolism: key
through the NF-kappaB pathway. J Neuroimmunol. 2017;305:108–14. pathophysiological modulators promote neurodegeneration, cognitive
52. Hirbec H E, Noristani HN, Perrin FE. Microglia Responses in Acute and impairment, and Alzheimer's disease. J Neurosci Res. 2017;95(4):943–72.
Chronic Neurological Diseases: What Microglia-Specific Transcriptomic 78. Nasrallah I, Dubroff J. An overview of PET neuroimaging. Semin Nucl Med.
Studies Taught (and did Not Teach) Us. Front Aging Neurosci. 2017;9:227. 2013;43(6):449–61.
Du et al. Translational Neurodegeneration (2018) 7:2 Page 7 of 7

79. Deverman BE, Patterson PH. Cytokines and CNS development. Neuron. 110. Quigley EMM. Microbiota-brain-gut Axis and neurodegenerative diseases.
2009;64(1):61–78. Curr Neurol Neurosci Rep. 2017;17(12):94.
80. Stephan AH, Barres BA, Stevens B. The complement system: an unexpected 111. Cattaneo A, et al. Association of brain amyloidosis with pro-inflammatory
role in synaptic pruning during development and disease. Annu Rev gut bacterial taxa and peripheral inflammation markers in cognitively
Neurosci. 2012;35:369–89. impaired elderly. Neurobiol Aging. 2017;49:60–8.
81. Lui H, et al. Progranulin deficiency promotes circuit-specific synaptic 112. Park AM, et al. Helicobacter pylori and gut microbiota in multiple sclerosis
pruning by microglia via complement activation. Cell. 2016;165(4):921–35. versus Alzheimer's disease: 10 pitfalls of microbiome studies. Clin Exp
82. Elmer BM, McAllister AK. Major histocompatibility complex class I proteins in Neuroimmunol. 2017;8(3):215–32.
brain development and plasticity. Trends Neurosci. 2012;35(11):660–70. 113. Chen F, et al. Could the gut microbiota reconcile the oral bioavailability
83. Erickson MA, Dohi K, Banks WA. Neuroinflammation: a common pathway in conundrum of traditional herbs? J Ethnopharmacol. 2016;179:253–64.
CNS diseases as mediated at the blood-brain barrier. 114. Zheng X, et al. Thinking outside the brain for cognitive improvement: Is
Neuroimmunomodulation. 2012;19(2):121–30. peripheral immunomodulation on the way? Neuropharmacology.
84. Banks WA. The blood-brain barrier in neuroimmunology: Tales of separation 2015;96(Pt A):94–104.
and assimilation. Brain Behav Immun. 2015;44:1–8. 115. Yang WT, et al. Chinese herbal medicine for Alzheimer's disease: clinical
85. Collins SM, Surette M, Bercik P. The interplay between the intestinal evidence and possible mechanism of neurogenesis. Biochem Pharmacol.
microbiota and the brain. Nat Rev Microbiol. 2012;10(11):735–42. 2017;141:143–55.
86. Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut
microbiota on brain and behaviour. Nat Rev Neurosci. 2012;13(10):701–12.
87. Sampson TR, Mazmanian SK. Control of brain development, function, and
behavior by the microbiome. Cell Host Microbe. 2015;17(5):565–76.
88. Bhattacharjee S, Lukiw WJ. Alzheimer's disease and the microbiome.
Front Cell Neurosci. 2013;7:153.
89. Belkaid Y, Harrison OJ. Homeostatic immunity and the microbiota.
Immunity. 2017;46(4):562–76.
90. Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation.
Cell. 2014;157(1):121–41.
91. Tomkovich S, Jobin C. Microbiota and host immune responses: a love-hate
relationship. Immunology. 2016;147(1):1–10.
92. Agace WW, McCoy KD. Regionalized development and maintenance of the
intestinal adaptive immune landscape. Immunity. 2017;46(4):532–48.
93. Erny D, et al. Host microbiota constantly control maturation and function of
microglia in the CNS. Nat Neurosci. 2015;18(7):965–77.
94. Ivanov II, et al. Induction of intestinal Th17 cells by segmented filamentous
bacteria. Cell. 2009;139(3):485–98.
95. Sudo N, et al. Postnatal microbial colonization programs the hypothalamic-
pituitary-adrenal system for stress response in mice. J Physiol.
2004;558(Pt 1):263–75.
96. O'Mahony SM, et al. Serotonin, tryptophan metabolism and the brain-gut-
microbiome axis. Behav Brain Res. 2015;277:32–48.
97. Praveen V, Praveen S. Microbiome-gut-brain Axis: a pathway for improving
brainstem serotonin homeostasis and successful autoresuscitation in SIDS-A
novel hypothesis. Front Pediatr. 2016;4:136.
98. Jiang XG, et al. Research progress in anti-inflammation of vagus nerve and
neurotransmitter ach. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue.
2003;15(1):59–61.
99. Das UN. Vagus nerve stimulation, depression, and inflammation.
Neuropsychopharmacology. 2007;32(9):2053–4.
100. Browning KN, Verheijden S, Boeckxstaens GE. The Vagus nerve in appetite
regulation, mood, and intestinal inflammation. Gastroenterology.
2017;152(4):730–44.
101. de Haan JJ, et al. Exploring the link between inflammation and the vagus
nerve. J Intern Med. 2010;267(1):130–1.
102. Hoeger S, et al. Modulation of brain dead induced inflammation by vagus
nerve stimulation. Am J Transplant. 2010;10(3):477–89.
103. Mirakaj V, et al. Vagus nerve controls resolution and pro-resolving mediators
of inflammation. J Exp Med. 2014;211(6):1037–48.
104. Gordon JI, et al. The human gut microbiota and undernutrition. Sci Transl
Med. 2012;4(137):137ps12.
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