Alzheimer's Disease

Question 1

What is Alzheimer’s disease?

Answer 1

• most common type of dementia
• impairs memory and other mental functions
• progressive neurodegenerative disorder

Question 2

What are the stages of neurodegeneration and where in the brain does it occue?

Answer 2

Early (entorhinal cortex)
- memory and learning; thinking and planning
Mild to moderate (limbic system)
- language problems, sense of surroundings
Severe (neocortex)
- lose ability to communicate, care for themselves, recognize friends and family

Question 3

What are senile plaques and what is their pathology?

Answer 3

alzheimer’s pathology
- extracellular
- composed of cleaved beta amyloid

Question 4

What are neurofibrillary tangles?

Answer 4

• intracellular cells
• composed of Tau

Question 5

What is beta amyloid?

Answer 5

• originates from transmembrane protein APP
• APP cleaved by secretases to form beta amyloid
• abnormal aggregates of Ab make up senile plaques
• mutations in APP or secretases cause early-onset (hereditary) Alzheimer’s disease

Question 6

What is Tau?

Answer 6

• microtubule associated protein important for microtubule stability
• Tau forms aggregates which make up neurofibrillary tangles in AD

Question 7

What is Tau’s structure and aggregation?

Answer 7

• natively unfolded protein with very little structure

Question 8

What happens when Tau is hyperphosphorylated?

Answer 8

• inhibits tau’s activity and leads to microtubule instability
• promotes aggregation with other tau molecules

Question 9

What is the hypothesized amyloid cascade?

Answer 9

Hypothesis: amyloid aggregates cause damage to neurons
improper APP processing -> increased amyloif beta aggregation -> aggregates impair neuronal function and cause inflammation/oxidative injury -> cause disruption of Tau and aggregation -> neuronal death

Question 10

What is the alternative amyloid hypothesis using toxic oligomers? What is the evidence?

Answer 10

small alpha-beta oligomers have a toxic effect on neurons
- oligomers can bind receptors and disrupt cell signaling
- oligomers can disrupt synapses and impair Tau function and calcium homeostasis

Question 11

What is the alternative tau hypothesis?

Answer 11

Tau is the primary cause of AD
- Tau aggregation correlates with dementia severity/type
- mutant tau models show neuronal loss that can be rescues with drugs that prevent Tau aggregation