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Flashcards in Ger 3 Alzheimer's Deck (73)
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1

What is the main RF for ALzheimer's Disease?

AGE

2

How many new cases per 100,000 people after age 65?

1275

3

What does the incidence of disease do every 5 years after age 65?

DOUBLES

4

After age 85, what % of the population receives this diagnosis?

33%

5

What things are associated with aging, thus leading to AD?

1. Oxidative stress
2. Impaired folding function of the ER
3. Impaired proteosome

6

What is the prognosis for most with Alzheimer's disease?

For most, it is death within 3-9 years, depending on the severity and progression of the disease

7

What is the most common pathological finding of AD?

Most common finding is aggregated beta-amyloid deposits leading to plaques and dystrophic neurites in neocortical terminal fields...often thought that the imbalance between AB production and clearance leads to accumulation

8

What are truncated proteins due to?

Proteolysis of amyloid precursor protein by...
1. Beta-site precursor protein-cleaving enzyme-1 (BACE-1)
2. Beta-secretase
3. Gamma secretase (contains presenilin-1...catalytic core)
*These 3 are in order

9

What are beta-amyloid deposits?

Natural products of metabolism and are between 36-43 AA in length

10

What do beta-amyloid proteins normally do at the synapse?

Dampen over-excited neurons

11

Which beta-amylod protein is more aggregation prone and damaging (toxic to cells)?

Beta-amyloid 42

12

Which beta-amyloid protein is more prevalent?

Beta-amyloid 40

13

With regards to beta-amyloid, what is thought to lead to disease state(AD)?

Over-production and lack of clearance is what is thought to lead to the disease state ...oxidative stress, impaired folding function of the ER and impaired proteasome functioning are all associated with aging, thus leading to AD

14

What are 2 pathological forms that beta-amyloid can aggregate into?

1. Fibrils --> Beta- pleated sheets --> Insoluble plaques
2. Monomers/oligomers --> Intermediate assemblies

15

Which pathological form of beta-amyloid is most toxic to synapses?

Monomers/Oligomers --> Intermediate assemblies
-The severity of cognitive effects is dependent on the concentration of soluble oligomers, no the overall beta-amyloid load

16

What 2 enzymes normally degrade beta-amyloid monomers and oligomers?

1. Neopresilyn
2. Insulin degrading enzyme
*Deficiencies in these enzymes may lead to accumulation of beta-amylod proteins

17

What is another pathological finding seen in AD?

Neurofibrillary tangles

18

Where are neurofibrillary tangles seen in AD?

Neo-temporal lobe structures (pyramidal neurons)

19

What are neutofibrillary tangles made of?

Hyper-phosphorylated Tau proteins

20

What is tau a normal constituent of?

Microtubules

21

Are neurofibrillary tangles specific for AD?

No... but they are a predictor in the severity of the disease

22

What does hyperphosphorylated Tau do in cells?

It is insoluble and will aggregate into paired helical structures and no longer associate with microtubules

23

In AD, are there mutations to Tau protein?

No, just aggregation into intermediate groups (In Parkinson Disease, there are mutations)

24

Are the intermediate aggregations of Tau cytotoxic?

Yes... (like beta-amyloid)

25

What tests might be good indicators for those with mild cognitive impairment?

T181 and T231

26

Which happens first...beta-amylod aggregation or Tau?

Beta-amyloid aauggregation precedes Tau

27

Does beta-amyloid induced degeneration of neurons require Tau?

YES

28

What is AD primarily a disease of?

Synaptic failure...hippocampal synapses begin to decline in patients with mild cognitive impairment

29

What are the 2 effects of beta-amyloid oligomers on the synapse?

1. Decreases long term potentiation and dendritic spines while simultaneously increasing long term depression
2. Pre-synaptic transmission is decreased as is post-synaptic glutamate receptor ion currents

30

What are glutamate receptor ion currents most likely lost due to?

Endocytosis of NMDA receptors and alpha-amino-5-hydroxy-5-methyl-5-isoxazole-propionic acid surface receptors