AD

Question 1

what is dementia ?

Answer 1

progressive loss of cognitive and intellectual functions without impairment of perception or consciousness

Question 2

what are the causes of dementia?

Answer 2

caused by a afriety of disorders including severe infections and toxins but most commonly associated with structural brain disease

Question 3

what is dementia characterised by?

Answer 3

• disorientation
• impaired memory
• judgement
• intellect

Question 4

what are the range of disease in dementia and that could act as cause?

Answer 4

1. Alzheimers disease
2. Vascular dementia
3. mixed - AD + VD
4. dementia with levy bodies
5. parkinsons dementia
6. fronto-temporal dementia (FTD)

Question 5

what are the macroscopic neuropathological hallmarks of AD?

Answer 5

1. cortex atrophy, hippocampus atrophy by 4-8% a year
2. deeper and wider sulci
3. smaller gyri

Question 6

which region is not affected in AD?

Answer 6

• cerebellum not affected in AD therefore used as controls in some studies

Question 7

what are the microscopic neuropathological hallmarks of AD?

Answer 7

plaque = amyloidpathy, extracellular 
tangles = tauopathy, intracellular

Question 8

what is the break staging?

Answer 8

neurofibrillary tangles had characteristic distribution pattern in six stages
Stage 1 and 2 – trans entorhinal, clinically silent
Stage 3 and 4 ) – limbic, in developing AD
Stage 5 and 6 – neocortical, fully developed AD

Question 9

what is CAA?

Answer 9

cerebro amyloid antipathy

• cerebral hypoperfusion due to accumulation ot tau around affected arteriole
• demonstrated several years before the onset of clinical AD

Question 10

what are proteinopathies seen in brain disease?

Answer 10

1. Lewy bodies (alpha syncuclein) - PD, LBD
2. TDP43 inclusions - ALS, FTD
3. FUS - ALS, FTD
4. Tau protein - AD, FTD, CBD

Question 11

what are the misfolded proteins in AD?

Answer 11

1. beta amyloid
2. hyperphosphorylated tau
3. alpha-synuclein
4. TDP-43

Question 12

what are the three main mutations that were found in early onset Alzheimers (EOAD)?

Answer 12

1. Amyloid precursor protein - APP ~50mutations
2. Presenilin 1 ~220 mutations
3. Presenilin 2 ~15 mutations

Question 13

the mutation of the early onset Alzheirmer’s (EAOD) is mainly

1. Familial AD (FAD)
2. sporadic AD (SAD)

Answer 13

1. Familial AD (FAD)

Question 14

on which chromosome is APP gene found?

Answer 14

chromosome 21, 18 axons in man and is highly conserved

Question 15

what is the structure of APP?

Answer 15

• transmembrane protein with large extracellular domain

- consists of a N and C terminal with alpha, beta and gamma site on the Abeta domain

Question 16

how many isoforms are present in APP and how long is the shortest one?

Answer 16

8 isoforms

shortest one - 695AA (highly expressed in brain)

Question 17

APP is not just expressed in brain but is concentrated at synapses also?
A. True
B. False

Answer 17

A. True

Question 18

what and how are the two products obtained from APP processing?

Answer 18

1. soluble APPalpha - the proteolytic activity (cutting by proteases) at the alpha site results in soluble APPalpha
2. soluble abeta - the proteolytic activity at beta and gamma cleavage site results in soluble abeta

Question 19

what is the function of

1. soluble APPalpha
2. soluble abeta

Answer 19

1. soluble APPalpha - mediates neuronal growth
2. soluble abeta (1-40,1-42) - when liberated they stick to each other forming aggregates and plaques which result in neuronal loss

Question 20

where are they most likely to play a role?

1. abeta1-40
2. abeta1-42

Answer 20

1. abeta1-40 in CAA (cerebro amyloid angiopathy)

2. abeta1-42 in brain parenchyma

Question 21

which enzyme mediates the proleptic activity at the gamma cleavage site?

Answer 21

gamma secretase

Question 22

why do APP mutations cause AD?

Answer 22

~50 mutations in ~120 families and almost all dominant

Question 23

what type of proteases are PSEN1 and 2?

Answer 23

aspartyl proteases

Question 24

how many components are present in gamma secretase and which is they key one?

Answer 24

• 4 components

- key one = presenilin 1, forms the catalytic of subunit go gamma secretase

Question 25

what are the following features of PSEN1? 1. chromosome 2. axons 3. mutations

Answer 25

1. chromosome 14q 2. 12 axons 3. 220 mutations - the most common form in FAD >50% cases

Question 26

what is the role of GWAS?

Answer 26

to identify SNPs and other variants in DNA associated with a disease but cannot specify casual genes on their own

Question 27

what is tauopathy composed of and it forms into what?

Answer 27

composed of hyperphosprylated tau protein which forms into paired helical filaments

Question 28

what is the structure of tau? 1. on which chromosome 2. axons 3. isoforms

Answer 28

- tau protein located on chromosome 17q of MAPT gene in humans - 11 axons and 6 isoforms

Question 29

what does the hyperphosphorylation of tau result in?

Answer 29

1. self assembly to PHFs/SF (paired helical filament/ straight filament) 2. sequestration of normal tau, MAP1 and MAP2 and consequent disruption of MTs

Question 30

what is the number of moles of phosphate per mole of tau in healthy and AD individuals?

Answer 30

healthy individual - 2-3 moles of phosphate per mole of tau | AD - this rises to to 3-4 fold

Question 31

how does tau protein mediate self assembly?

Answer 31

some tau protein in AD brain becomes truncated which seems to promote self assembly

Question 32

where is tau mislocalised in AD?

Answer 32

usually found in axons but in AD they translocate to different places like spine

Question 33

what is the prionic spread of tau?

Answer 33

it is the idea that tau is transmitted b/w neurons, thus supporting the 'neuronal connectivity' account of pathology spreading

Question 34

how do we know that tau has prionic spread?

Answer 34

inoculation of tau aggregates isolated from the AD patients brain/ tau transgenic mice/ other tauopathies into human tau transgenic mice or WT type mice induces time-dependent spread of tau pathology from the inoculation site to synoptically connected brain regions

Question 35

how to stop AD?

Answer 35

1. stop APP from being turned into abtea fragments/ stop the abeta formation from APP 2. destroy the abeta fragments 3. stop the abtea from assembling into toxic forms (stop the plaque formation) 4. understand how abeta causes trouble (neuronal toxicity) and then intervene 5. stop tau pathology (+ kinase block - to prevent the phosphorylation) 6. stop the prionic spread of tau

Question 36

how does one show new drugs work?

Answer 36

1. memory tests - ADAS-Cog, MMSE | 2. brain imaging - MRI, PET

Question 37

how are the animal models of dementia created?

Answer 37

- genetically modify mice to produce dementia like pathology in the brain - by introducing mutations that produce inherited human dementia into mice - e.g. APP knock in mice for AD

Question 38

what are the ways to measure mouse memory?

Answer 38

1. Morris water maze test 2. PDAPP mouse 3. imaging single mouse neurons working in the intact brain 4. testing drugs

Question 39

what is the difference between beta and gamma secretase?

Answer 39

1. beta secretase enzyme is BACE1 and gamma secretase consists of PSEN, PEN2 2. beta secretase cleaves the APP protein at N terminal (~1) and gamma secretase cleaves at C terminal (~40)