Pathogenesis of dementia

Question 1

List three major neurodegenerative diseases associated with abnormal protein conformations?

Answer 1

Azheimer’s disease

Creutzfeldt-Jakob disease

Parkinson’s disease

Question 2

Describe the genetic risk factors for Alzheimer’s disease?

Answer 2

Chromosome 21 (APP mutations)

Chromosome 19 (Apolipoprotein E)

Chromosome 14 (PS 1)

Chromosome 1 (PS 2)

Down’s syndrome (trisomy 21)

Question 3

Describe the environmental risk factors for developing Alzheimer’s disease?

Answer 3

Question 4

Which has a larger impact on the development of AD: genetic or environmental risk factors?

Answer 4

Genetic factors

Question 5

Describe the four basic types of AD?

Answer 5

Amnestic (temporal)

Visuospatial (R>L)

Aphasic (L>R)

Frontal

Question 6

What are the two major pathologic lesions in the brain in AD?

Answer 6

Amyloid-beta plaques

Neurofibrillary tangles

Question 7

Describe how amyloid-beta plaques form in AD?

Answer 7

Question 8

How do neurofibrillary tangles form in AD?

Answer 8

Aggregation of tau, thought to be driven by amyloid beta peptide

Question 9

Which part of the amyloid protein is thought to induce the pathogenesis of AD?

Answer 9

After short peptode released from TM domain, reforms as tetramer or dimer

These oligomers get stuck on or near synapses and interfere with normal processes of transmission, leading to degeneration

Question 10

Describe one approach to taregtting the Ab oligomer in treating AD?

Answer 10

MPAC

Metal-protein attenuating compound

Small proteins that can cross BBB and cause compete with metals for binding sites on Ab dimers > dimers fall apart and can be processed

Question 11

Describe the current approach to diagnosing AD?

Answer 11

1) Measuring Ab peptide in CSF
2) Radiolabelled ligand which binds amyloid filaments > PET scan

Question 12

Describe how Ab levels vary in Alzhemier’s compared to health controls?

Answer 12

AD patients sit above arbitrary cutoff of 1.5

However, lots of healthy controls and patients with MCI also sit above this cutoff > are on their way to developing AD

Question 13

Describe the progression of Ab deposition over time?

Answer 13

Takes thirty years to move from completely normal to full blown AD

Takes 20 years to move from 1.5 cutoff to full blown AD

Question 14

Within which category of diseases does Creutzfeldt-Jakob disease belong?

Answer 14

Transmissible Spongiform Encephalopathies

Question 15

What is the natural host of CJD?

Answer 15

Humans

Question 16

In which countries does CJD occur?

At what rate?

Answer 16

Sporadically all around the world

1 in 1 million

Question 17

What is kuru characterised by?

Answer 17

Tremors and shaking

Cerebellar degeneration

Question 18

Briefly describe how kuru was acquired?

Answer 18

Infectious disease

Women and children exposed when they dismembered dead bodies

Question 19

Describe the similarirties in causes between kuru and BSE?

Answer 19

Kuru: feeding humans to humans

BSE: feeding cattle to cattle

Both due to cannabilism

Question 20

Describe the histological appearrance of brains affected by BSE?

Answer 20

Vacuoles developing within neuropil

Fluid filled, membrane bound bound holes sitting in the cells of neurons

Many astrocytes reacting to damage to nerve cells

Question 21

Which molecule is responsible for the development of BSE?

How does it differ to normal?

Answer 21

PrPres (prion protein)

Has beta pleated sheet, which makes it insoluble and resistant to degradation

Has ability to induce normal form (PrPc) to take on same shape

Question 22

What is vCJD?

Answer 22

Variant CJD

New form of human BSE affecting young individuals after infected BSE carcasses entered human food supply

Presented in form similar to kuru - cerebellar predominance, neuropsychiatric phenomena

Question 23

Why are people who lived in the UK (in specified period) prohibited from donating blood?

Answer 23

vCJD blood is infectious

Estimated incubation period is 6-15 years > peak exposure of BSE was in 1988-1993 > blood infectivity now at peak

Question 24

Describe the brain area affected by PD?

Answer 24

Dopaminergic neurons in substantia nigra

Question 25

Which molecule, other than DA, has been implicated in the development of PD?

Answer 25

a-synuclein

Question 26

Describe the molecular pathway which underlies PD?

Answer 26

a-synuclein comes into contact with Da > becomes redox active > combination induces a-synuclein to fold abnormally > becomes insoluble

Lewy Body inclusions