3. Alzheimer

Question 1

What is the main risk factor for Alzheimer Disease?

Answer 1

AGE –> incidence of disease doubles every 5 years after the age of 65

Question 2

What are three main processes that are associated with aging and lead to AD?

Answer 2

1. oxidative stress
2. impaired folding function of the ER
3. impaired proteosome functioning

Question 3

What is the prognosis of AD?

Answer 3

death within 3-9 years, depending on the severity and progression of the disease

Question 4

What is the most common pathological finding in AD?

Answer 4

aggregated B-amyloid deposits that lead to plaques and dystrophic neurites in neocortical terminal fields. It is thought that B-amyloids aggregate d/t imbalance between production and clearance.

Question 5

What enzymes lead to proteolysis of amyloid precursor proteins (APP) and truncated proteins as a result?

Answer 5

1. Beta-site Precursor Protein-Cleaving Enzyme-1 (BACE-1)
2. B-secretase
3. gamma-secretase

Question 6

Which B-amyloid protein is more aggregation prone? Which is more prevalent?

Answer 6

AB42: aggregation
AB40: prevalent

Question 7

What are the two main processes that lead to aggregation?

Answer 7

1. fibrils –> B-pleated sheets –> insoluble plaques

2. monomers/oligomers –> intermediate assemblies* - most toxic against synapses

Question 8

What is the severity of cognitive defects in AD dependent on?

Answer 8

The concentration of soluble oligomers (rather than the overall B-amyloid protein concentration)

Question 9

What enzyme deficiencies may lead to B-amyloid protein accumulations?

Answer 9

Neoprsilyn and Insulin Degrading Enzyme - normally these degrade AB monomers and oligomers

Question 10

Where are neurofibrillary tangles found and what are they composed of?

Answer 10

They are found in neo-temporal structures and they are composed of hyper-phosphorylated Tau proteins. They are not specific for AD, but they are a predictor of severity of AD.

Question 11

What is the relationship between B-amyloid proteins and Tau proteins?

Answer 11

B-amyloid aggregation precedes Tau, but B-amyloid induced degeneration of neurons requires Tau

Question 12

What structures begin to decline in function d/t AD-induced cognitive impairment?

Answer 12

hippocampal synapses undergo decreased long term potentiation and decreased spines with increased long term depression

Question 13

What are neurotrophins and how are their functions altered in AD?

Answer 13

Neurotrophins promote the proliferation, differentiation, and survival of neurons and glia. They are important for memory, learning, and behavior. Heavily reduced neurotrophin receptors are seen in the cholinergic neurons of the forebrain of AD pts.

Question 14

What happens to cholinergic receptors in AD pts and what kind of drug can be given to improve Sx?

Answer 14

B-amyloid proteins bind cholinergic receptors and cause decreased transmission. Cholinesterase inhibitors like rivastigmine can be given as an antidote.

Question 15

How does B-amyloid affect the mitochondria?

Answer 15

B-amyloid notably damages Cytochrome C in neural mitochondria. This damages the electron transport chain which leads to energy loss within the cells.

Question 16

What events lead to cell apoptosis in AD?

Answer 16

superoxide radicals in the mitochondria and damage to cytochrome C

Question 17

What are insulin signaling pathway disturbances that are risk factors for AD?

Answer 17

glucose intolerance and Type II diabetes

Question 18

How do high glucose levels in the brain lead to damage?

Answer 18

High glucose damages the hippocampus, upregulates Tau protein, and depletes levels of Insulin Degradign Enzyme (needed for depletion of B-amyloid)

Question 19

Pts with what kind of disease make up 60-90% of the AD population?

Answer 19

Pts with vascular disease, the vast majority with major infarcts. Cerebral amyloid angiopathy may affect up to 90% of pts

Question 20

What two cells are chronically activated that lead to inflammatory damage and how do they cause damage?

Answer 20

Microglia and astrocytes are prevalent in fibrillar plaques. They will release pro-inflammatory cytokines like IL-1, IL-6, and TNF-a

Question 21

Elevation of what ion leads to aggregation of B-amyloid and amyloidogenesis?

Answer 21

cytosolic Ca2+

Question 22

What cholesterol transporter increases the risk of AD and B-amyloid deposition by 19x?

Answer 22

ApoE

Question 23

Mutation in what gene may lead to increased risk for AD?

Answer 23

presenilin-1

*other risk genes include Apolipoportein J, TOMM40, and Soritilin Related Receptor

Question 24

What medication has been shown to cause Tau instability and B-amyloid polymerization?

Answer 24

general anesthesia