Introduction to Amyloidosis 4.

Beta-2 Microglobulin:
o A component of MHC Class I; accumulates in patients on long-term dialysis due to inadequate renal
 Definition: Amyloidosis is a group of disorders characterized by the extracellular clearance. Deposits in joints (dialysis-related amyloidosis).
accumulation of misfolded, insoluble proteins known as amyloid fibrils. These Chronic Renal Failure / Long-Term Dialysis→ ↓ Clearance of β2-Microglobulin (MHC Class I Subunit)→ β2-Microglobulin
proteins aggregate and deposit in tissues, leading to structural disruption and organ dysfunction. Accumulates in Blood→ Misfolding & β-sheet Formation→ Amyloid Fibrils Form→ Deposits in Joints & Tendons→ Dialysis-
 Histology: Amyloid deposits stain red with Congo red and show apple-green birefringence under polarized light. Related Amyloidosis (Joint Pain, Carpal Tunnel)
These deposits are primarily found in the basement membrane (extracellular matrix).
5. Amyloid Precursor Protein (APP  Aβ (Amyloid-beta)
2. Structural and Chemical Characteristics of Amyloid type of amyloid that contributes to Alzheimer’s disease & it’s quite distinct from AL, AA, or ATTR amyloids.
 Amyloid deposits are composed of:
o 95% fibrillary proteins: Misfolded beta-sheet-rich proteins that aggregate in a stack-like (duct-shaped) Amyloid Precursor Protein (APP)→ Cleaved abnormally by β-secretase and γ-secretase→ Forms Aβ peptides (esp. Aβ₄₂)→
configuration. Aβ peptides misfold into β-pleated sheets→ Aggregate into soluble oligomers → insoluble fibrils→ Form extracellular
o Amyloid P component: A serum glycoprotein. amyloid plaques in the brain→ Neuronal damage, inflammation, and synaptic dysfunction→ Progressive cognitive decline
o Glycosaminoglycans (GAGs): Aid in complex stability and staining properties (iodine reactivity is due to this (Alzheimer’s Disease)
component).  APP is a normal membrane protein found in neurons.
 These aggregates disrupt normal tissue architecture and compress surrounding cells, causing atrophy and organ  In Alzheimer’s, it’s processed abnormally, producing the neurotoxic Aβ₄₂ fragment.
dysfunction.  Aβ accumulation leads to amyloid plaques, a hallmark of Alzheimer’s.
 Coexists with tau protein tangles (intracellular), which disrupt microtubules in neurons.

3. Types of Amyloid and Protein Precursors

 Over 25 known amyloid precursor proteins in humans. 4. Classification of Amyloidosis
 Amyloidosis can be systemic (multi-organ) or localized (restricted to one tissue). Primary Amyloidosis (AL type):
Most Common Types:  Often linked to monoclonal plasma cell disorders.
1. AL (Amyloid Light Chain):  monoclonal disorders, one plasma cell clone expands abnormally and produces a monoclonal protein (M-protein or
o Derived from immunoglobulin light chains (lambda or kappa), typically due to plasma cell dyscrasias (e.g., paraprotein).
multiple myeloma)  Genetic or sporadic.
o Form amyloid fibrils → organ dysfunction Secondary Amyloidosis (AA type):
o Seen in 10-15% of multiple myeloma and 20-25% of other light chain diseases.  Result of chronic inflammatory diseases (e.g., infections, autoimmune conditions).
o Test used: Serum Free Light Chain (FLC) assay  Common in familial Mediterranean fever, rheumatoid arthritis, chronic osteomyelitis.
Plasma Cell Clone → Overproduction of Free Light Chains (κ or λ)→ Misfolding of Light Chains→ Aggregation into β-pleated Hereditary (Familial) Amyloidosis:
Sheets→ Formation of Amyloid Fibrils→ Extracellular Deposition in Tissues→ Disruption of Organ Structure & Function→ Organ  Autosomal dominant or recessive.
Damage (Kidney, Heart, Nerves, etc.)  Most often due to mutated transthyretin, leading to familial amyloid polyneuropathy (FAP).
2. AA (Amyloid A):  Also includes mutations in MEFV gene in familial Mediterranean fever.
o Derived from serum amyloid A protein, an acute phase reactant produced in the liver during chronic Localized Amyloidosis:
inflammation (e.g., TB, rheumatoid arthritis).  Found in a single organ (e.g., brain in Alzheimer's disease, heart in isolated cardiac amyloidosis).
Chronic Inflammation→ ↑ IL-6 / IL-1 / TNF-α → Liver produces Serum Amyloid A (SAA)→ Excess SAA not cleared properly→
Misfolds into β-pleated Sheets→ Forms AA Amyloid Fibrils→ Deposits in Organs (esp. Kidneys, Liver, Spleen)→ Systemic 5. Pathogenesis
Amyloidosis & Organ Dysfunction  Misfolding Mechanisms:
3. ATTR (Transthyretin): o Overproduction of normal proteins (SAA, light chains).
o Transthyretin is a transport protein for thyroxine and retinol-binding protein. Mutant or wild-type TTR misfolds, o Mutant proteins prone to aggregation (mutated TTR).
forming amyloid fibrils. o Incomplete proteolysis (e.g., beta-2 microglobulin).
o Mutant ATTR: Familial amyloid polyneuropathy (FAP). o Template-induced misfolding (prion-like mechanism).
Mutant ATTR (Familial Amyloid Polyneuropathy) TTR Gene Mutation→ Unstable Transthyretin Tetramer→ Tetramer Dissociates  Sequence:
into Monomers→ Misfolding & β-sheet Aggregation→ Amyloid Fibril Formation (ATTR)→ Deposits in Nerves, Heart, GI Tract→ 1. Protein misfolds (secondary structural change to beta-sheets).
Polyneuropathy & Cardiomyopathy 2. Oligomers form.
o Wild-type ATTR: Senile systemic amyloidosis (common in elderly men) Aging Process (No Mutation) 3. Fibrils assemble.
Wild-Type ATTR (Senile Amyloidosis)→ Normal TTR Slowly Misfolds→ ATTR Amyloid Forms→ Deposits Primarily in Heart→ 4. Fibrils deposit extracellularly, disrupting tissue.
Restrictive Cardiomyopathy in Elderly Men
6. Clinical Manifestations
 Systemic Amyloidosis (AL, AA, ATTR):
o Kidney: Proteinuria, nephrotic syndrome. 11. Prion Diseases Overview
o Heart: Restrictive cardiomyopathy, arrhythmias, heart failure. Defini on: Prion diseases (aka transmissible spongiform encephalopathies) are a group of rare, fatal neurodegenera ve
o Liver/Spleen: Hepatosplenomegaly, elevated alkaline phosphatase. disorders caused by misfolded prion proteins that can induce other normal proteins to misfold.
o Peripheral Nerves: Carpal tunnel syndrome, polyneuropathy.
Core Mechanism
o GI: Malabsorption, hepatomegaly.
 Normal prion protein (PrP^C) → alpha-helical
o Skin: Purpura (especially periorbital).
 Abnormal prion protein (PrP^Sc) → beta-pleated sheet
 Specific Statistics (AL):
 PrP^Sc is resistant to proteases, heat, and UV, and induces misfolding of PrP^C →
o Lipid nephrosis: 80%
aggregation in the brain.
o Heart failure: 40%
 Mechanism: Misfolded prion protein (PrP^Sc) converts normal PrP^C into PrP^Sc.
o Hepatosplenomegaly: 38%
Pathology
o Carpal tunnel syndrome: 85%
 Spongiform encephalopathy: Vacuoles in gray matter
 No inflammatory response
7. Diagnosis
 Neuronal loss and gliosis
1. Biopsy of a ected tissue:
o Congo red staining → apple-green birefringence under polarized light.
Transmission Types
2. Typing of Amyloid:
o Immunohistochemistry, mass spectrometry. Form How It Arises
o Rule out AL with serum/urine protein electrophoresis. Sporadic Most common; cause unknown (e.g., sporadic CJD)
o Genetic testing for TTR mutations. Inherited Due to PRNP gene mutation (e.g., familial CJD, FFI, GSS)
3. Organ assessment: Acquired Via contaminated food, tissue (e.g., vCJD, Kuru, iatrogenic CJD)
o Renal, cardiac, hepatic involvement tests.

Human Prion Diseases

8. Treatment Approaches
 Goal: Reduce precursor protein production, inhibit fibril formation, manage organ damage.
Disease Features
AL Amyloidosis: Creutzfeldt-Jakob Disease (CJD) Rapid dementia, myoclonus, ataxia, EEG changes (periodic sharp waves)
 Chemotherapy targeting plasma cells (e.g., bortezomib, cyclophosphamide). Variant CJD (vCJD) Linked to BSE (mad cow), younger patients, psychiatric symptoms first
AA Amyloidosis: Kuru Linked to cannibalism (Papua New Guinea), cerebellar signs
 Treat underlying inflammation.
Fatal Familial Insomnia (FFI) Thalamic degeneration, progressive insomnia, autonomic failure
 IL-6 inhibitors (e.g., tocilizumab) to suppress SAA production.
ATTR Amyloidosis: Gerstmann-Sträussler-Scheinker (GSS) Ataxia, dementia; familial; slower course
 Mutant TTR: Liver transplant.
 Wild-type TTR: TTR stabilizers (tafamidis), gene silencing (patisiran). Diagnosis
Beta-2 Microglobulin Amyloidosis:  Clinical + history + rapid progression
 Optimization of dialysis techniques.  EEG: Sharp wave complexes (CJD)
Experimental Therapies:  MRI: Hyperintensity in basal ganglia/thalamus
 Peptides that disrupt beta-sheet formation.  CSF markers: 14-3-3 protein, tau
 Cross-linking inhibitors.  Definitive: Brain biopsy or post-mortem histology
No Cure
9. Prognosis  Always fatal
 Systemic AL amyloidosis: Median survival ~2 years if untreated.  Supportive care only
 Earlier diagnosis improves outcomes.  Strict sterilization needed (autoclaving insu icient)
Animal Models:
10. Amyloidosis in Neurodegenerative Disease  Scrapie: In sheep, used to study pathogenesis.
 Alzheimer's Disease:  Bovine Spongiform Encephalopathy (BSE): Mad cow disease, transmissible to humans (variant CJD).
o Accumulation of beta-amyloid plaques and tau protein neurofibrillary tangles. Key Features:
o Leads to amyloid angiopathy, cognitive decline, and risk of cerebral hemorrhage.  No immune response (no nucleic acids).
o Down syndrome: Early onset Alzheimer-like pathology due to overexpression of APP on chromosome 21.  Long incubation periods.
  Spongiform encephalopathy (vacuolated brain tissue).
Transmission:
 Ingestion (e.g., infected beef), iatrogenic (e.g., dura mater grafts), familial mutations.
Resilience:
 Resistant to heat, UV, and most proteases.