Amyloid Diseases 2 Flashcards
Systemic Amyloid Diseases examples
1) Dialysis-related amyloidosis (DRA)
2) Transthyretin (TTR) amyloidosis
Dialysis-Related Amyloidosis (DRA)
A complication of renal dialysis affecting upto 100% of subjects on long-term renal dialysis - caused by a build-up of B2-microglobulin (B2M):
- The 99 amino acid protein is normally removed from blood by kidneys
- Dialysis can’t efficiently remove it: it accumulates in the blood eventually accumulating as amyloid plaques in the osteoarticular tissues (joints)
- Amyloid deposition causes severe skeletal morbidity: bone cysts, fractures, cartilage thinning
B2M forming fibrils and affecting bones in DRA
IV collagen and Glycosaminoglycans (GAGs) promote amyloid formation (the 2 are abundant in joints)
The 6 amino acid truncation also contributes to amyloid formation
Bm2 can inhibit osteoclast formation:
- cell type that normally remodels bone
- May explain role in destroying bones & joints
Treating DRA
Renal Transplant
- best therapeutic option
- Best way of removing B2M
Doxycyclin inhibits amyloid assembly in vitro
- clinical trials show pain relief and improved joint movement
Transthyretin (TTR) amyloidosis
TTR is a transport protein present in serum (binds thyroxine and retinol binding protein)
- produced primarily by liver
- Amyloid deposition can occur in a number of sites
» associated with peripheral neuropathy and cardiomyopathy
Cause of TTR amyloidosis
- Senile form associated with old age
- Familial forms associated with mutations in gene encoding Transthyretin (multiple allele types)
Amyloid formation in TTR
TTR is a tetrameric protein so amyloid formation requires the dissociation of monomers from tetramer
- mutation destabilised tetramer
- amyloid assembly from production of oligomers (can be toxic/contribute to pathological effects)
Treatment of TTR
Liver transplant
- Ensures wt TTR is produced
Stabilisation of TTR tetramer with small molecule (Tafamadis)
- can dissociate to form oligomers otherwise
- FDA approved in 2017
Metabolic disorders: Type 2 Diabetes
Characterised by chronic insulin resistance and progressive loss of B-cell function and B-cell mass in pancreas
- impaired insulin release and hyperglycaemia
- consequences include: vision loss, renal failure, amputation, CVD, stroke…
Type 2 Diabetes and Amylin amyloid
Amylin is a 37-peptide protein co-secreted with Insulin that readily forms amyloid in vitro
- Amylin amyloid formation occurs in type 2 diabetes, with amyloid fibrils occurring inside the Islets of Langerhan
- Plaques present in at leasat 1 islet of 90% of type 2 patients
Extensive Amylin amyloid association with Islet dysfunction
May require insulin replacement therapy upon dysfunction of islets
- Amylin oligomers are toxic and damage membranes
- Fibrils on membranes damage membranes
- Increase severity of Type 2 Diabetes by killing B-cells
Alzheimer’s disease
Most common type of dementia affecting ~850,000 in the UK
- incidence increases dramatically with age
- most common cause of dementia: serious deterioration in mental functions as nerves in the brain die/lose connection (loss of hippocampus first)
Histopathological hallmarks of Alzheimer’s
- Extracellular (senile) plaque of Amyloid-beta peptides
- Neurofibrilliary tangles of misfolded Tau within cell body and dendrites of neurones
Amyloid-beta (Ab) formation
Ab derived from processing of the Amyloid Precursor Protein (APP)
- Ab in 42-peptide form is more dangerous than 40-peptide form
2 processing pathways:
1) Anti-amyloidogenic
- Cleaved by ADAM10 & g-secretase
- Produce non-disease related fragments
2) Pro-amyloidogenic
- Cleaved by BACE1 & g-secretase
- generates 40 or 42 peptide long Ab fragments
The Amyloid Cascade Hypothesis
Proposes Ab amyloid formation drive disease as their oligomers are toxic
fibrils also produce Tau plaques in neurones
Alzheimer’s genetics
90% of cases are sporadic
various genes linked (e.g. Down’s trisomy 21)
Apolipoprotein E4 allele
Treating Alzheimer’s (targeting symptoms)
No cure, can only target symptoms:
- cholinesterase inhibitors increase acetylcholine levels to compensate for levels being reduced
- N-Methyl-D-Aspartate (NMDA) antagonists prevent degeneration of cholinergic neurones
Treating Alzheimer’s (targeting amyloid cascade)
This field of research is currently unsuccessful
- Targeting Ab peptides, enhancing immune response
- Targeting Tau accumulation
Parkinson’s Disease
Affecting 10 million people worldwide, is a movement disorder associated with the death of dopamine-producing (dopaminergic) neurones in the Substantia Niagra
- Symptoms: tremor, rigidity, postural instability, slowness of movement
- majority of cases are sporadic (increased incidence with age)
- subset of cases are due to mutation in a-synuclein
a-Synuclein forming amyloids in Parkinson’s
Form Lewy bodies in cytoplasm of affected neurones (also present in dementia)
- a-synuclein readily forms fibrils in vitro
- Mutation linked to early onset forms of disease: a-synuclein oligomers are toxic and disrupt neuronal membranes
Treating Parkinson’s
No cure, can only target symptoms:
- L-DOPA replacement therapy
- Inhibition of dopamine breakdown
- Dopamine agonists
- Dopa-decarboxylase inhibitor (DDCI)
Functional Amyloids examples
1) Pmel17 amyloid
2) Hormone storage
3) Curli fibres
Functional amyloids: Pmel17 amyloid
Found in melanocytes (pigment granules) and retinal pigment epithelium
- Amyloid fibrils where melanin is deposited
- mutation = loss of pigment
Functional amyloids: Hormone storage
Hormones are stored as amyloid fibrils in Pituitary Secretory Granules
- e.g. Prolactin, Beta-endorphin, oxytocin
- Upon secretion, the fibrils dissociate into monomers (due to increase in pH)
- Also evidence of glycogen and calcitonin
Functional amyloids: Curli fibres in E.coli
Functional for extracellular adhesion to host cells & forming a biofilm to improve attachment
- useful for pathogenicity
Amyloid-beta (Ab) as a functional fibril?
Evidence to be an antimicrobial agent
- oligomers and fibrils interact with microbial cell walls and viruses to inhibit their adhesion to host cells
