Alzheimer's Disease

Question 1

What are the 4 stages of Alzheimer’s Disease?

Answer 1

1. Predimentia (Mild Cognitive Impairment)
2. Mild Alzheimer’s
3. Moderate Alzheimer’s
4. Severe/Advanced Alzheimer’s

Question 2

Why are the costs of caring for dementia so much less expensive than Alzheimer’s Disease?

Answer 2

Because in the later stages of A.D. a patient requires ‘round-the-clock care

Question 3

What are neurofibril tangles (NFTs)?

Answer 3

NFTs contain paired helical filaments and are densely packed intracellular fibers composed of Tau

Question 4

What are senile plaques?

Answer 4

Extracellular deposits of protein fragments, made of β-amyloid peptide.

Aβ is a fragment of a precursor called “amyloid precursor protein” (APP).

Question 5

Which structures of the brain are affected in AD, and in which order are they affected?

Answer 5

The affected structures progress typically from the first the hippocampus or entorhinal cortex (EC), then association areas for senses or cortical areas for memory, and ultimately the brainstem.

Question 6

What are the known functions of βAPP?

Answer 6

βAPP decreases cuts of α-secretase and increases cuts of β-secretase and levels of Aβ42 by y-secretase

Question 7

Which derivatives of BAPP are formed from B-secretase and a-secretase, respectively?

Answer 7

An a-secretase cut cleaves beneath the extracellular tail, creating Soluble Amyloid Precursor Protein a (sAPPa) extracellularly.

A B-secretase cut will result in a cut of the extracellular tail, making an sAPPB and allowing for AB42 to be produced by y-Secretase.

Question 8

What neuronal damage is best correlated with dementia in AD?

Answer 8

eAβ: spine density, can interfere with receptor function, and decrease expression of NMDAR and AMPAR.

iAβ: decreases in neuron survival, causes axon transport issues, is linked to increases in tangle formation, and creates markers for apoptosis.

Question 9

Mechanisms of neural damage by intracellular and extracellular Aβ.

Answer 9

Extracellular Aβ decreases dendritic spine density, can interfere with receptor function, and decrease expression of NMDAR and AMPAR.

Intracellular Aβ decreases neuron survival, causes axon transport issues, is linked to increases in tangle formation, and creates markers for apoptosis.

Question 10

Which of either Y1472 or S1480 need to be phosphorylated to either increase NMDAR surface expression or decrease it?

Answer 10

Increase of NMDAR = Phosphorylation of Y1472 by Fyn, carried by Tau

Decrease of NMDAR = Phosphorylation of S1480, losing PSD-95 anchor and AP-2 binding

Question 11

What are the two categories of Alzheimer’s medication and for what are they beneficial?

Answer 11

Acetylcholinesterase inhibitors:

Show mild benefits of early dementia

NMDAR antagonists:

NMDA overstimulation will lead to too much Ca++ flow and create cytotoxicity

Used to help with moderate to severe dementia

Question 12

What are deficiencies of traditional hypothesis of plaques being the starting point for AD

Answer 12

1. Aβ accumulation may be a part of a response to infection
   a. Injection of bacteria into the brain will
   nucleate formation of plaques
   b. Many cases have viruses or bacterium at
   the center of plaque formations
   c. BBB becomes more permeable to
   bacterium with age
   d. There are strong correlations between
   gum disease and Alzheimer’s Disease
2. There are individuals that are 90+ y.o. with high plaque loads and no resulting signs of dementia or cognitive decline.
3. There have been 0 successful drug studies in finding a cure.