Cycle 9

Causes of Alzheimer’s

a. beta- amyloid plaques (APP)

b. neurofibrillary tangles (TAU)

Beta amyloid Plaques (APP)… Normal vs Problem

→ deregulation (increased) of APP

• APP sits on cell memb. of neuron and is needed for proper func.

APP needs to break down and regulate, then a new one transcribes/translates

Normal (two types)

1) alpha secretase + y-secretase enzymes cut APP very SPECIFICALLY into 2 soluble peptide pieces

2) beta secretase cuts at a different point, This forms longer + insoluble peptide. Amyloid Beta (which gets cleared by microglia, astrocytes and apolipoprotein E)

Problem

1) Over production of beta- secretase

2) Mutation in catalytic subunit of y-secretase

• precsenilin-1 (part that cuts APP), causing it to cut at 42A (forms plaque, due to ability to stick together)

3) A mutation in Apolioprotein E leads to alzheimer (in genetic form)

• happens cuz cant clear plaques/aggregates (clearance decreases, can’t keep up w/ production)

Orange presenilin-1

• catalytic subunit of y-secretase (active site)

• cutting off APP

• mutation here leads to alzheimers, drives to cut 42 AA

What does the Aβ40 : Aβ42 ratio indicate, and why is it important?

The Aβ40 : Aβ42 ratio reflects the balance between amyloid peptides produced from APP.

• Aβ40 = more common, less toxic

• Aβ42 = less common, more “sticky” and prone to forming plaques

👉 A lower ratio (more Aβ42) is associated with Alzheimer's disease, because Aβ42 aggregates and damages neurons.

Key idea:
More Aβ42 → more plaque formation → higher disease risk

Tau protein: hypophosphorylated vs hyperphosphorylated — what’s the difference? —> Neurofibrillary Tangles

Normal (hypophosphorylated tau):

• Few phosphate groups

• Binds microtubules → stabilizes them

• Normal neuron function

Disease (hyperphosphorylated tau):

• Too many phosphate groups

• Detaches from microtubules (TAU falls off and microtubule breaks down)

• Tau’s clump together forming tangles → neuron damage

Seen in: Alzheimer's disease

Key memory:
👉 Low phosphate = stable
👉 High phosphate = tangles

Cholinergic Neurons Normal

Normal:
Cholinergic neuron = releases Acetylcholine (ACh)

Steps:

1. ACh is released into the synapse

2. Binds to receptors on the next neuron

3. Signal is passed (memory, movement, attention)

4. ACh is broken down by acetylcholinesterase to stop the signal

Key idea:
👉 Release → bind → signal → breakdown

Cholinergic neurons NOT normal

1. ACh is released into the synapse

2. Binds to receptors on the next neuron

3. Signal is passed (memory, movement, attention)

4. ACh is broken down by acetylcholinesterase to stop the signal

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In Alzheimer's disease:

• Cholinergic neurons degenerate

• ↓ ACh levels

• CAT (Choline acetyl transferase) levels decrease so cannot make acetylcholine

• Aβ plaques + tau tangles disrupt signaling
  → impaired communication → memory loss

Key memory:
👉 Less ACh and CAT= worse signaling = memory decline

Acetylcholinesterase Inhibitors

• given to patient

• inhibits AChE

• keeps acetylcholine in receptor for longer (not breaking down by AChE)

Overall deterioration in cholinergic nerves and loss of memory

Neuron structure and how they communicate at synaptic cleft

Function:

Cell body (soma): Contains nucleus

Dendrites: Receives INPUT from other neurons + carries signal TOWARDS cell body

Axons: Conducts electrical impulses (action potential) AWAY from soma and to other neurons

Axon Hillock: Point where action potential is initiated

Myelin sheath: Insulates axon + increases speed

Axon terminals: Filled w/ neurotransmitters

How they communicate:

• Neurons communicate via neurotransmitters by presynaptic neuron to post synaptic neuron

• post synaptic sends signal

How do microglia, astrocytes and ApoE eliminate aggregates?

1) Resting microglia gets activated due to plaques

2) Once activated, it releases cytokines which activates astrocytes

3) Astrocytes release ApoE (gets rid of plaque)

• Astrocytes also releases glutamate (neurotransmitter which binds to NMDA allowing for signal to fire)

4) Glutamate activates neuron A LOT by binding to NMDA receptor

—> hyperexcited leads to neuron death

Common drugs for AD function

NMDA antagonists: → Binds to NMDA receptor + doesn’t lead to signal = no activation of neuron

Agonists: binds to neural receptor and forces signal

Anti-amyloid antibodies

• takes bio of disease + reverses it (plaque)

1) AAA is infused through the arm

2) Clears amyloid from brain/body

3)AAA binds to amyloid plaques formed + promotes removal of amyloid before plaques form

4) AAA trigger immune cells to clear amyloid plaques

Genetic risk factors

Down syndrome

• APP gene coded on chromo 21

• Increased APP expression = increased risk of early onset

Mutations in Presenilin 1 and 2

• Presenilin 1→ chromo 14, Presenilin 2 → chromo 1

• Found in familial AD, early onset

• Mutant y secretase produces larger AB peptides (42aa) leading to more aggregates

Inheritance of Apo E4

• Apo E gene —> chromo 19

• Apo EZ → RARE

• Apo E3 → Most common, efficient at removing AB aggregates

• Apo E4 → not effective at removing AB aggregates (Autosomal dominant form of inheritance)