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PATH30003- Frontiers in Human Disease > Lecture 1- Alzheimer's Disease > Flashcards

Lecture 1- Alzheimer's Disease Flashcards

1
Q

most common form of dementia

A

AD- 60-80%

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2
Q

early and late clinical symptoms of AD

A

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

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3
Q

2nd most common type of dementia

A

vascular dementia- 10%

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4
Q

what is vascular dementia?

A

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

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5
Q

symptoms of vascular dementia

A

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

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6
Q

major clinical symptom of PD

A

movement problems

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7
Q

characteristics of dementia with lewy bodies

A

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

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8
Q

characteristics of frontotemporal dementia (FTD)

A

changes in personality and behaviour, more aggressive than AD

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9
Q

what is mixed dementia?

A

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

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10
Q

characteristics of creutzfeldt-jakob disease (CJD)

A

rapidly fatal disorder, impairs memory and coordination, behaviour changes

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11
Q

characteristics of huntington’s disease

A

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

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12
Q

characteristics of Wernicke-Korsakoff syndrome

A

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

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13
Q

normal pressure hydrocephalus

A

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

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14
Q

dementia

A

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

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15
Q

3 major stages leading to AD

A
  1. pre clinical with no symptoms
  2. MCI- memory problems first sign
  3. clinical AD
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16
Q

clinical progression of AD

A

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

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17
Q

diagnosis of AD

A

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

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18
Q

sporadic and familial AD

A

sporadic-90%

familial-10%- typically earlier onset compared to sporadic

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19
Q

risk factors for AD

A 
ageing
gender (women higher risk)
elevated BP/CVD
head injury
education (lower risk) 
genetics
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20
Q

mutations that can cause AD

A

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

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21
Q

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

A

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)

22
Q

compare ApoE4 and ApoE2 alleles

A

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

23
Q

cell loss in AD

A

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

24
Q

what is the cholinergic hypothesis?

A

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

25
Q

molecules downregulated in cholinergic system

A

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

26
Q

major alterations in cholinergic system

A

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

27
Q

how does cholinergic pathway relate to AD?

A

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

28
Q

treatment targeting cholinergic system

A 
AChE inhibitors (Aricept)- increases ACh and enhances cholinergic activity
cholinergic precursors, cholinergic receptors agonists, NMDA receptor blockers
29
Q

protein aggregates in AD

A

NFT’s- intracellular, hyperphosphorylated tau

Amyloid plaques- extracellular, Abeta peptide

30
Q

2 phases in formation of amyloid

A

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

31
Q

what is the dye that indicates amyloid aggregation?

A

thioflavin-T

32
Q

consequence of adding pre-aggregated protein (Seeds)

A

accelerations aggregation, smaller lag phase

33
Q

what are the major forms of Abeta?

A

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

34
Q

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

A

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

35
Q

mutations near beta secretase

A

increase Abeta levels

36
Q

mutations near gamma secretase

A

increase Abeta42 levels

37
Q

presinilin mutations promote?

A

Abeta42 levels

38
Q

A673T carriers

A

protective- better cognition scores

39
Q

mutations near alpha secretase

A

affect aggregation

40
Q

describe tau phosphorylation in the leadup to AD

A

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

41
Q

tau and abeta pathology timeline

A

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
42
Q

changes in AD biomarkers

A

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

43
Q

oxidative stress in AD and evidence

A

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

44
Q

zinc and AD

A
  • 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
45
Q

copper and AD

A
  • reduction (sequestered to plaques)
  • promote tau aggregation and phosphorylation
  • binds Abeta, promotes Th-T negative aggregates
46
Q

iron and AD

A
  • 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
47
Q

neuroinflammation in AD

A

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
48
Q

pro-inflammatory cytokines in AD

A

TNF-alpha, IL-1beta, IL-6, IL-18

- pro-apoptotic, decrease LTP, increase Abeta synthesis, decrease clearance, increase tau phosphorylation

49
Q

TREM2

A
  • 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
50
Q

3 tests showing Abeta toxicity

A
  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
51
Q

APP:PS1 transgenic mice findings

A

Abeta drives tau pathology

Abeta mediated effects/toxicity require tau expression

PATH30003- Frontiers in Human Disease (20 decks)

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