Degenerative disease due to amyloid

Question 1

List some chronic degenerative diseases

Answer 1

Alzheimers
Parkinsons 
Huntingtons
T2D
Senile heart failure

Question 2

What does amyloid consist of?

Answer 2

Fibrillar deposits of abnormally folded host protein which provoke degenerative reactions

Question 3

Mechanisms of amyloid formation

Answer 3

1. misfolding from alpha helical secondary structure to beta rich (beta sheets can stack and so accumulate)
2. they gather into oligomers → then into protofibrils and then into fibrils
3. these acquire resistant to proteases and extracellular macrophages
4. they can be deposited (usually extracellularly) causing tissue damage and altered organ function

Question 4

Describe aetiology

Answer 4

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

Question 5

Which neurons are vulnerable to death in AD?

Answer 5

Neurons projecting from the entorhinal cortex to the dentate gyrus (hippocampal formation) and the principal neurons in the CA1 region of the hippocampus

Question 6

Discuss AD with regard to progressive cholinergic deficit

Answer 6

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

Question 7

What are the three elements that are thought to be prominent contributors to the development of AD?

Answer 7

• beta-amyloid
• apolipoportein E
• tau

Question 8

Describe beta amyloid

Answer 8

• pathogenic peptide derived from the proteolytic cleavage of amyloid precursor protein (APP) by enzymes (γ-secretases and β-secretases)

Question 9

What mutations affect amyloid in AD?

Answer 9

APP

PSEN1/PSEN2 (encoding secretases)

Question 10

What is APOE involved in with AD?

Answer 10

• usually normal catabolism of triglyceride-rich lipoproteins
• may act as a chaperone for amyloid beta

Question 11

Describe tau protein

Answer 11

• 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

Question 12

List one difference between amyloid beta and tau

Answer 12

amyloid beta - extracellular

tau - intracellular (tau is thought to make A beta diseases worse)

Question 13

What may be the efects of amyloid beta aggregation in the pathogenesis of AD?

Answer 13

• 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

Question 14

Risk factors for AD

Answer 14

• cholesterol
• obesity
• T2D
• hypertension
• smoking

Question 15

Symptoms of PD

Answer 15

• tremor at rest
• shuffling gate
• rigidity

Question 16

Describe briefly the mechanism behind familial PD

Answer 16

mutations in SNCA which encodes alpha-synuclein, a major component of Lewy bodies - accumulate in substantia nigra

Question 17

What are diseases which are secondary to chronic inflammation characterised by? What does this normally do? Where does it accumulate?

Answer 17

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

Question 18

Which disease is peripheral amyloidosis associated with?

Answer 18

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

Question 19

Discuss dialysis associated amyloidosis

Answer 19

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

Question 20

List prion disease features

Answer 20

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

Question 21

Discuss AD histopathology

Answer 21

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

Question 22

What do prions occur from?

Answer 22

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.

Question 23

What can a prion be defined as?

Answer 23

A prion is defined as “a small proteinaceous infectious particle which resists
inactivation by procedures that modify nucleic acids”.

Question 24

Symptoms of CJD

Answer 24

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)

Question 25

How do you get vCJD?

Answer 25

SPread is believed to be primarily due to eating bovine spongiform encephalopathy-infected beef (mad cow disease)
Blood transfusions

Question 26

Difference between vCJD and CJD?

Answer 26

• has an average age of death <30
• longer duration of illness
• strongly linked to food exposure