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Pharmacology Test #6 > Alzheimer's > Flashcards

Flashcards in Alzheimer's Deck (51)
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1

AD symptoms

1. memory loss (especially recent memories)
2. impaired ability to learn, reason
3. impaired ability to carry out daily activities; confusion, untidiness
4. anxiety, suspicion, hallucinations
5. motor dysfunction can also occur in late-stage disease

2

Environmental risk factors of AD

1. Age
2. Low educational level
3. Reduced mental activity in late life
4. Reduced physical activity in late life
5. Risks for vascular disease
6. Hear injury

3

AD neuropathology

1. loss of brain volume
2. amyloid plaques and neurofibrillary tangles
3. synapse loss

4

Amyloid plaques

extracellular; consist of amyloid-beta peptide (Abeta)

5

Neurofibrillary tangles

intracellular; consist of hyperphosphorylated tau

6

Neuropathology primarily affects which areas of high cognitive function?

1. Entorhinal cortex
2. Hippocampus
3. Basal forebrain cholinergic systems
4. Neocortex
5. Nucleus basalis

7

A striking feature of neurons with neurofibrillary tangles and neurons in the vicinity of amyloid plaques is

destruction of synapses

8

Synapse loss results in

1. reduced levels of neurotransmitters - especially acetylcholine, but also serotonin, norepinephrine, and dopamine
2. dysregulated glutamate -> excess excitotoxicity and neurotoxicity

9

Genetic evidence that suggests a key role for Abeta?

1. Mutations in the gene encoding the Abeta precursor protein, APP, are linked to early onset AD
2. Trisomy 21 is associated with an AD-like phenotype, and the APP gene is located on chr 21
3. Mutations in the gene encoding presenilin proteins involved in cleaving Abeta from APP are linked to early onset AD

10

Abeta peptide is released from

the transmembrane amyloid precursor protein (APP) by the activity of beta-secretase (BACE1) and gamma-secretase

11

Cleavage of APP by alpha-secretase in the middle of the Abeta segment releases

a non-amyloidogenic (non-toxic) fragment

12

Mutations in the APP gene favor

cleavage by beta- or gamma-secretase, resulting in the production of more Abeta or more Abeta42

13

What do mutations in the gene encoding presenilin-1 or presenilin-2 (PSEN1 or PSEN2) do?

alter APP cleavage by gamma-secretase, resulting in the production of more Abeta or more Abeta42

14

Abeta aggregation is thought to promote

tau hyperphosphorylation, leading to neurofibrillary tangle formation, cytoskeletal anomalies, and disruption of axonal trafficking

15

What is Entresto?

Valsartan + Sacubitril: new CHF drug

16

What is the concern about Entresto?

It is a Neprilysin inhibitor and there's concern that inhibitors of Neprilysin could contribute to AD

17

Neurofibrillary tangle formation results in

cytoskeletal defects

18

What happens in unhealthy areas of the brain where tangles have accumulated?

the cytoskeletal tracks are disrupted and disorganized, resulting in trafficking defects and synaptic dysfunction

19

Abeta is thought to induce neurotoxicity indirectly by

triggering microglial activation, a process that is probably aimed at clearing amyloid from the brain

20

Activated microglia release

1. pro-inflammatory cytokines (PGs, interleukins, TNF-alpha) that cause neuroinflammation
2. reactive nitrogen species and reactive oxygen species that cause oxidative stress

21

CV risk factors in AD

1. elevated LDL and decreased HDL increase AD risk
2. vascular disease may accelerate AD pathogenesis (decreased nutrient delivery to the brain, decreased Abeta clearance, increased Abeta accumulation)

22

How does diabetes increase the risk of AD?

defects in insulin signaling may lead to accumulation of toxic glucose metabolites in the brain, decreased Abeta clearance

23

ApoE responsible for

transporting cholesterol in brain (LDL); defects in cholesterol metabolism may alter membrane structure and function, which in turn affects Abeta deposition

24

Three ApoE isoforms

ApoE2, ApoE3, and ApoE4

25

Significance of individuals with one or two ApoE4 alleles?

One or two ApoE4 alleles increase the risk of AD

26

Significance of individuals with an ApoE2 allele

decreases the risk of AD

27

Cholinesterase inhibitors block

The conversion of acetylcholine to acetic acid and choline; thereby compensating for the loss of acetylcholine that results from the degenration of cholinergic nerve terminals in AD

28

Cholinesterase inhibitors

1. Donepezil (Aricept)
2. Rivastigmine
3. Galantamine

29

Donepezil (Aricept)

specific, reversible inhibitor of acetylcholinesterase

30

Rivastigmine

inhibits acetylcholinesterase and butyrylcholinesterase