Alzheimer’s disease – cellular mechanisms and iPSC-based disease modeling

Question 1

What are the most common drugs used against Alzheimer’s disease, and what do they target?

Answer 1

Aducanumab and Lecanemab, both are targeting beta-amyloid plaques

Question 2

What are the known causes of Alzheimer’s disease?

Answer 2

• Age
• Positive family history
• Down syndrome
• APP, PSEN1/2 mutation
• APP duplication
• APOE4 allele, CLU, BIN1

Question 3

What mutation can protect a person from Alzheimer’s disease?

Answer 3

APP-A673T: mutation in specific location of APP - a protective mutation

Question 4

Explain the the cholinergic hypothesis of Alzheimer’s disease

Answer 4

A decreased level of acetylcholin is seen in AD, and there is a strong correlation between this neurotransmitter and cognitive function, and it is important for learning and memory

Question 5

Explain the amyloid hypothesis of Alzheimer’s disease

Answer 5

The hypothesis states that beta-amyloid production and accumulation (either oligometric of fibrillar beta-amyloid peptide) is responsible for AD

Question 6

How is beta-amyloid normally cleared from the body?

Answer 6

In the blood: systemic clearance in kidney and liver
In brain: degradation by microglia and astrocytes

Question 7

What peptide create beta-amyloid, and which enzyme facilitates cleavage

Answer 7

A beta-sectetase cuts the peptide (APP), and can create different versions of it

Question 8

Why does the PSEN mutation cause early-onset Alzheimer’s?

Answer 8

This mutations related to secretases will cause ‘wrong’ versions of the APP peptide to be cleaved, causing more beta-amyloid

Question 9

What role does Tau play in Alzheimer’s disease? (The Tau hypothesis)

Answer 9

Tau will normally bind and stabilize microtubles, if too much Tau become phosphorylated, it will destabilize them.
The phosphorylated Tau will also become tangled, creating neurofibrillary tangles (NFTs).
NFTs lead to increased synaptic and neuronal loss and therefore cognitive impairment.

Question 10

What are NFTs?

Answer 10

Neurofibrillary tangles, created when phosphorylated Tau becomes tangled. NFTS lead to increased synaptic and neuronal loss and therefore cognitive impairment.

Question 11

Explain the calcium hypothesis of Alzheimer’s disease

Answer 11

Dysregulation of calcium signalling in the cell is a part of the pathogenesis of AD.
If you have too much calcium in the cells, it will cause stuff like beta-amyloid accumulation and hyperphosphorylation of Tau and neuronal death

Question 12

What cell types are iPCs often used for, when studying Alzheimer’s disease?

Answer 12

• Astrocytes
• Microglia
• Neurons
• Organoids
• Neuronal progenitor or stem cells

Question 13

What changes in astrocytes during Alzheimer’s disease?

Answer 13

Astrocytes normally connect to multiple neurons and help them, but during AD this is disrupted
- They release more beta-amyloid in AD
- They release different cytokines in AD
- They show altered calcium homeostasis in AD

Question 14

What changes in microglia during Alzheimer’s disease?

Answer 14

Microglia usually clears beta-amyloid and other dangerous stuff from the brain, during AD this is disrupted
- Phagocytosis of beta-amyloid and Tau oligomers
- Reduced beta-amyloid internalization

Question 15

What is TREM2 and how is it related to Alzheimer’s disease?

Answer 15

This receptor is important for the microglial respons to beta-amyloid pathology