Lecture 1- Alzheimer's Disease

Question 1

most common form of dementia

Answer 1

AD- 60-80%

Question 2

early and late clinical symptoms of AD

Answer 2

early- difficulty remembering recent events, apathy, depression
late- impaired communication, confusion, behaviour changes, difficulty swallowing

Question 3

2nd most common type of dementia

Answer 3

vascular dementia- 10%

Question 4

what is vascular dementia?

Answer 4

problems in vascular system of brain (blockage, damage to blood vessels–>infarcts, strokes in brain)

Question 5

symptoms of vascular dementia

Answer 5

impaired judgement and ability to plan steps to complete task (not memory loss like AD)

Question 6

major clinical symptom of PD

Answer 6

movement problems

Question 7

characteristics of dementia with lewy bodies

Answer 7

memory loss/thinking problems (AD) and symptoms of sleep disturbance, hallucinations, parkinsonian movement features (shuffling gait)

Question 8

characteristics of frontotemporal dementia (FTD)

Answer 8

changes in personality and behaviour, more aggressive than AD

Question 9

what is mixed dementia?

Answer 9

both AD related neurodegenerative processes and vascular related processes, sometimes include LB deposits; common cause of dementia in elderly

Question 10

characteristics of creutzfeldt-jakob disease (CJD)

Answer 10

rapidly fatal disorder, impairs memory and coordination, behaviour changes

Question 11

characteristics of huntington’s disease

Answer 11

abnormal involuntary movements, mood changes, severe decline in thinking/reason skills

Question 12

characteristics of Wernicke-Korsakoff syndrome

Answer 12

chronic memory disorder- severe deficiency of thiamine (vit B1) due to alcohol misuse; other social/thinking skills relatively unaffected

Question 13

normal pressure hydrocephalus

Answer 13

buildup of fluid in brain; difficulty walking, memory loss, urinary incontinence

Question 14

dementia

Answer 14

significant impairment of at least 2 key mental functions- memory, communication/language, attention, reasoning/judgement, visual perception

Question 15

3 major stages leading to AD

Answer 15

1. pre clinical with no symptoms
2. MCI- memory problems first sign
3. clinical AD

Question 16

clinical progression of AD

Answer 16

prodromal period- up to 30yrs, decline in cognition but still healthy, may develop MCI and then go on to AD
mild AD, moderate AD, severe AD

Question 17

diagnosis of AD

Answer 17

during mild AD stage; cognitive exams (mini mental state exam, clock drawing test)

Question 18

sporadic and familial AD

Answer 18

sporadic-90%

familial-10%- typically earlier onset compared to sporadic

Question 19

risk factors for AD

Answer 19

ageing
gender (women higher risk)
elevated BP/CVD
head injury
education (lower risk) 
genetics

Question 20

mutations that can cause AD

Answer 20

APP (Chr21), PSEN1 (Chr14), PSEN2 (Chr1), Down syndrome (3 copies of APP gene, Chr21), duplication of APP locus

Question 21

compare early onset , late onset AD and common variants/mutations

Answer 21

early onset- rare mutations, have high risk for AD e.g. PSEN1/2, APP
late onset- medium risk for AD e.g. ApoE4 (two copies), ADAM10
common variants- dont cause AD but increase risk e.g ApoE4 (one copy)

Question 22

compare ApoE4 and ApoE2 alleles

Answer 22

ApoE4- increases risk of developing AD
- Abeta has a lower affinity to LRP1 than ApoE4; Abeta doesnt get degraded by LRP1
ApoE2- protective form
- Abeta has a higher affinity than ApoE2 therefore gets degraded
ApoE KO mice- protected from Abeta deposition

Question 23

cell loss in AD

Answer 23

loss of neurons in brain space for memory and language, loss of synaptic connections, loss of cell bodies of neurons

Question 24

what is the cholinergic hypothesis?

Answer 24

there is a loss of cholinergic function in AD
ACh neurotransmitter released at synapse, interacts with receptors and mediates signal
cholinergic pathway projects to thalamus and serves important functional roles in conscious awareness, attention and working memory

Question 25

molecules downregulated in cholinergic system

Answer 25

choline acetyltransferase (ChAT), acetylcholinesterase (AChE)- breakdown ACh therefore less ACh

Question 26

major alterations in cholinergic system

Answer 26

impaired ACh release impaired Choline uptake deficits in expression of nicotinic and muscarinic receptors dysfunctional neutrophrin and axonal support

Question 27

how does cholinergic pathway relate to AD?

Answer 27

Abeta peptide interacts with cholinergic receptors and affects their function cholinergic pathway drives disease process early on and associated with cognitive impairment but NOT causing AD

Question 28

treatment targeting cholinergic system

Answer 28

``` AChE inhibitors (Aricept)- increases ACh and enhances cholinergic activity cholinergic precursors, cholinergic receptors agonists, NMDA receptor blockers ```

Question 29

protein aggregates in AD

Answer 29

NFT's- intracellular, hyperphosphorylated tau | Amyloid plaques- extracellular, Abeta peptide

Question 30

2 phases in formation of amyloid

Answer 30

nucleation phase- monomer, misfolded monomer, dimer elongation phase- oligomer, protofibrils, mature fibrils amyloid (beta sheet structures in amyloidgenic form)

Question 31

what is the dye that indicates amyloid aggregation?

Answer 31

thioflavin-T

Question 32

consequence of adding pre-aggregated protein (Seeds)

Answer 32

accelerations aggregation, smaller lag phase

Question 33

what are the major forms of Abeta?

Answer 33

Abeta40- more abundant Abeta42- more amyloidgenic, more neurotoxic increase in 42:40 ratio- predictive of AD

Question 34

describe the cleaving of APP for both amyloidgenic and non-amyloidgenic forms of Abeta

Answer 34

amyloidogenic- cleavage at beta-secretease and gamma-secretase, forms sAPPbeta, abeta and AICD non-amyloidogenic- cleavage at alpha-secretsae and gamma secretase, get sAPPalpha P3 (truncated form of abeta, not toxic) and AICD

Question 35

mutations near beta secretase

Answer 35

increase Abeta levels

Question 36

mutations near gamma secretase

Answer 36

increase Abeta42 levels

Question 37

presinilin mutations promote?

Answer 37

Abeta42 levels

Question 38

A673T carriers

Answer 38

protective- better cognition scores

Question 39

mutations near alpha secretase

Answer 39

affect aggregation

Question 40

describe tau phosphorylation in the leadup to AD

Answer 40

tau- microtubule binding protein, regulates axonal transport, movement of motor proteins (dyenin, kinesin) , can modulate interaction between mitochondria and microtubule tau is normally phosphorylated- regulated by kinases and phosphatases; foetal tau more phosphorylation increased phosphorylation decreases interactions with microtubules-->leads to NFTs

Question 41

tau and abeta pathology timeline

Answer 41

tau immunoreactivity precedes Abeta amyloid plaques - intraneuritic pretangle tau, then first plaques, then NFTs develop - tau pathology possible since childhood, exacerbated by Abeta after given threshold of Abeta reached

Question 42

changes in AD biomarkers

Answer 42

CSF tau- increases, as neurons die, release tau extracellularly CSF Abeta- decreases, deposited and retained in brain hippocampal volume- reduced, cellular loss glucose metabolism- decrease over time, decrease energy

Question 43

oxidative stress in AD and evidence

Answer 43

pathological hallmarks- ROS affects mitochondria, damages cells, lipids, DNA evidence- mitochondrial dysfunction e.g. reduction in brain glucose metabolism prior to onset of disease, reduction in antioxidant response molecules, increased levels of oxidative stress markers

Question 44

zinc and AD

Answer 44

- increase in bulk zinc, reduction in synaptic (sequestered in amyloid plaques) - mis-compartmentalisation; interact with GABA/NMDA inappropriately - promote aggregation and phosphorylation of tau - binds Abeta, promotes Th-T positive aggregates

Question 45

copper and AD

Answer 45

- reduction (sequestered to plaques) - promote tau aggregation and phosphorylation - binds Abeta, promotes Th-T negative aggregates

Question 46

iron and AD

Answer 46

- increased levels in brain due to breakdown in system - Iron(III)-induce aggregation of hyperphosphorylated tau - enriched in NFTs->can produce ROS - ferritin (binds most iron in brain), increases ventricle size

Question 47

neuroinflammation in AD

Answer 47

Amyloid plaques and NFT's co-localise (TLR's and RAGE) and activate microglia and astrocytes-->prolonged activation-->inflammatory response (cytokines) - reactive gliosis - altered synaptic pruning - can become independent of Abeta-->chronic inflammation

Question 48

pro-inflammatory cytokines in AD

Answer 48

TNF-alpha, IL-1beta, IL-6, IL-18 | - pro-apoptotic, decrease LTP, increase Abeta synthesis, decrease clearance, increase tau phosphorylation

Question 49

TREM2

Answer 49

- triggering receptor expressed on myeloid cells 2 - single transmembrane cell surface protein - expressed on microglia, can bind to ApoE, upregulated near Abeta plaques (amyloid deposition correlates with TREM2 expression) - heterozygous carriers- increases risk of late onset AD - variants affect the way TREM2 regulates inflammatory response

Question 50

3 tests showing Abeta toxicity

Answer 50

1. cell viability (MST assay)- Abeta42 to neurons in culture, decrease in viability 2. LTP (long term potentiation)- Abeta42 to neurons, decrease LTP, inhibition of memory formation 3. Synaptotoxicity- addition of Abeta, loss of spines from neurons

Question 51

APP:PS1 transgenic mice findings

Answer 51

Abeta drives tau pathology | Abeta mediated effects/toxicity require tau expression