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
