53 - Pathogenesis of Dementia

Question 1

Abnormal gene product associated with Parkinson’s

Answer 1

Alpha synuclein

Question 2

Age risk factor for Alzheimer’s after 50 years

Answer 2

Exponential doubling prevalence of Alzheimer’s with each decade after 50 years

Question 3

Genes associated with increased Alzheimer’s disease risk

Answer 3

Apolipoprotein E
Presenilin 1
Presenilin 2
APP mutations

Question 4

Chromosomal defect associated with Alzheimer’s

Answer 4

Trisomy 21.

Invariably get early-onset Alzheimer’s

Question 5

Examples of risk factors for Alzheimer’s

Answer 5

Under seven years of education
Head trauma
Smoking
Vascular disease
Diabetes
Antioxidants. 

All of these give marginal increases in risk. Still don’t know major environmental risks for Alzheimer’s

Question 6

Four basic types of Alzheimers

Answer 6

1) Amnestic (most common)
2) Visuospatial (affects right more than left)
3) Aphasic (affects left more than right)
4) Frontal

Question 7

Where does Alzheimer’s often begin?

Answer 7

Temporal lobes, then spreads

Question 8

What is APP?

Answer 8

Precursor protein, which is cleaved to form amyloid beta.

Question 9

Neurofibrillary tangles

Answer 9

Aggregates of tau, a microfilament-associated protein

Question 10

What do presenilin 1 and 2 affect?

Answer 10

Formation of APP

Question 11

What do ApoE mutations affect?

Answer 11

How amyloid beta is cleared from brain

Question 12

Possible cleavages of amyloid beta

Answer 12

Can be cleaved in the transmembrane domain, which leads to non-amyloidogenic pathway.

Can be cleaved in extracellular domain to form amyloid beta monomers, which aggregate into plaques.

Question 13

Cellular components which cleave Abeta

Answer 13

Presenillin 1 and 2, with two other proteins.

Form a protein involved in proteolytic cleavage

Question 14

What does Abeta do that can cause neurodegeneration?

Answer 14

Oligomer attaches to plasma membrane, interferes with synaptic transmission.
With age, oligomers aren’t cleared effectively, allowing buildup

Question 15

Metal-protein attenuating compound

Answer 15

Small molecule that interferes with ability of amyloid beta to form oligomers.

Question 16

How can Abeta be imaged in vivo?

Answer 16

Inject radio-labelled small molecules (carbon-11 Pittsburgh Compound B) that can bind to amyloid in brain.

This can be visualised with CT

Question 17

How long does it take, roughly, from detectable levels of Abeta to complete Alzheimer’s?

Answer 17

~20 years

Question 18

MAb administered against amyloid (in development)

Answer 18

Solanezumab

Question 19

Effects of Solanezumab

Answer 19

Disease-modifying, not just symptom-modifying

Question 20

Incidence of CJB in Australia

Answer 20

~1/1,000,000

Question 21

How long can it take between exposure to infectious prions and manifestation of disease?

Answer 21

Several decades

Question 22

What lead to the bovine spongiform encephalopathy epidemic in the UK?

Answer 22

Feeding dead cattle to other cattle.

Question 23

Change in the brains of those with spongiform prion diseases

Answer 23

Small vacuoles in brain tissue (hence ‘spongiform’).

Characteristic of toxic challenge to neurons.

Question 24

Molecular process of CJD

Answer 24

Conversion of cellular prion protein (PrPc) to PrPres.
Alpha helices in PrPc change conformation to beta sheets, forming PrPres.

PrPres can catalyse PrPc conformation change to PrPres, hence infectiousness.

Question 25

Pathogenic mutations in PrP

Answer 25

Methionine mutations instead of a valine (homozygous) puts one at much greater risk of conversion from PrPc to PrPres

Question 26

Difference between sporadic CJD (sCJD) and CJD from eating infected meat (cows infected with BSE) (vCJD)

Answer 26

Higher replication of PrPres in tonsils and lymphatic tissues.
Makes it more transmissible though blood

Question 27

Where is alpha-synuclein expressed in the brain?

Answer 27

All synaptic membranes, helps vesicles dock onto internal surface of plasma membrane to release neurotransmitters

Question 28

histological appearance of alpha-synuclein aggregates

Answer 28

Lewy bodies in substantia nigra

Question 29

How is alpha-synuclein thought to aggregate?

Answer 29

In the presence of metals or dopamine, are induced to form oligomers, which then assemble into fibrils.