Degenerative disease due to amyloid Flashcards
List some chronic degenerative diseases
Alzheimers Parkinsons Huntingtons T2D Senile heart failure
What does amyloid consist of?
Fibrillar deposits of abnormally folded host protein which provoke degenerative reactions
Mechanisms of amyloid formation
- misfolding from alpha helical secondary structure to beta rich (beta sheets can stack and so accumulate)
- they gather into oligomers → then into protofibrils and then into fibrils
- these acquire resistant to proteases and extracellular macrophages
- they can be deposited (usually extracellularly) causing tissue damage and altered organ function
Describe aetiology
Infections (propagated conformational change e.g. vCJD - Prion Disease)
Genetic (mutation/covalent modification - inherited predisposition for misfolding e.g. FFI)
Secondary to chronic disease (excess production of serum proteins such as Ig, where the clearance mechanisms become saturated and therefore the proteins are not cleared)
Consequence of ageing and failure of normal clearance mechanisms/processing/chaperones
Which neurons are vulnerable to death in AD?
Neurons projecting from the entorhinal cortex to the dentate gyrus (hippocampal formation) and the principal neurons in the CA1 region of the hippocampus
Discuss AD with regard to progressive cholinergic deficit
A characteristic of AD is a relatively selective loss of cholinergic neurons in the basal forebrain, leading to a reduction in the cholinergic innervation of the cortex and hippocampus
Attempts to alleviate this loss using cholinesterase inhibitors, tacrine or donepezil, has resulted in modest improvement in cognitive function in some patients
What are the three elements that are thought to be prominent contributors to the development of AD?
- beta-amyloid
- apolipoportein E
- tau
Describe beta amyloid
- pathogenic peptide derived from the proteolytic cleavage of amyloid precursor protein (APP) by enzymes (γ-secretases and β-secretases)
What mutations affect amyloid in AD?
APP
PSEN1/PSEN2 (encoding secretases)
What is APOE involved in with AD?
- usually normal catabolism of triglyceride-rich lipoproteins
- may act as a chaperone for amyloid beta
Describe tau protein
- involved in the stabilisation of microtubules in neurons
- thought to be involved in AD when it detaches from microtubules and forms insoluble aggregates int he brain
List one difference between amyloid beta and tau
amyloid beta - extracellular
tau - intracellular (tau is thought to make A beta diseases worse)
What may be the efects of amyloid beta aggregation in the pathogenesis of AD?
- oxidative damage
- altered synaptic plasticity
- excitotoxicity
- neruonal cell death
- change in membrane permeability
- impaired trafficking of proteins for degradation
- protective attempts by astrocytes
- chronic inflammation
Risk factors for AD
- cholesterol
- obesity
- T2D
- hypertension
- smoking
Symptoms of PD
- tremor at rest
- shuffling gate
- rigidity
Describe briefly the mechanism behind familial PD
mutations in SNCA which encodes alpha-synuclein, a major component of Lewy bodies - accumulate in substantia nigra
What are diseases which are secondary to chronic inflammation characterised by? What does this normally do? Where does it accumulate?
Deposition of insoluble aggregations of serum amyloid A - a normally soluble acute phase protein which increases 100 fold in inflammation and functions to transport cholesterol to the liver for bile secretion, immune cell recruitment and induction of ECM degrading enzymes
- heart, spleen, liver and kidney
- disease manifestation can therefore include renal damage, proteinurea or nephrotic syndrome
- these are especially seen in developing countries
Which disease is peripheral amyloidosis associated with?
ype II diabetes mellitus - Beta cell failure correlates with formation of pancreatic islet amyloid deposites of amylin - normally co-secreted with insulin; the peptides aggregate to form beta cell toxic fibrils
Discuss dialysis associated amyloidosis
Common in hemodialysis receiving adults - those receiving this for more than 5 years might be subjected to B2 microglobulin accumulation in the blood (this is not cleared by the dialysis barrier) and aggregation into large insoluble, damaging deposits (bone, joints and tendons) resulting in pain and stiffness. Bone cysts might lead to unexpected fractures
List prion disease features
Progressive
• Irreversible
• Fatal
• Vacuolating neurodegeneration
• Often amyloid plaques
• Often diffuse and/or focal accumulations of protease-resistant PrP
• Infectivity associated with abnormal PrP, no DNA
Discuss AD histopathology
Extracellular amyloid plaques between neurons composed of fibrils of proteolytic fragments of APP
• Plaques of unknown pathological significance
• Intracellular neurofibrillary tangles composed of fibrils of hyper-phosphorylated Tau protein (microtubule
associated protein) in neurons
• Collapse of neuronal structure & connexions
• Local chronic inflammatory responses by glial cells
What do prions occur from?
occur due to misfolding of the
normal cellular membrane protein, PrP c . When this occurs, it is converted from a normal α-
helical structure to a β-pleated sheet structure, known as PrP sc . This is able to form fibrillary
extracellular aggregates which can cause neural destruction and inhibit proper neural
function.
What can a prion be defined as?
A prion is defined as “a small proteinaceous infectious particle which resists
inactivation by procedures that modify nucleic acids”.
Symptoms of CJD
rapid delerium/dementia, hallucination and confusion, speech impairment, disorientation and ataxia, jerky movements and changes in gait -> loss of many functions and death. Startle myoclonus (i.e. weird contractions if you go up behind them and clap)
How do you get vCJD?
SPread is believed to be primarily due to eating bovine spongiform encephalopathy-infected beef (mad cow disease)
Blood transfusions
Difference between vCJD and CJD?
- has an average age of death <30
- longer duration of illness
- strongly linked to food exposure
