Lecture 10: Alzheimer's Disease: Neural Stem Cells

Question 1

What is Alzheimer Disease (AD)?

Answer 1

It is an age-related progressive brain disorder that gradually destroys a person’s memory and ability to learn, reason, make judgements, communicate, and carry out daily activities.
Lots of atrophication occurs by the time patients pass away.
Age is a risk factor but getting old does not mean one gets AD.

Question 2

What are risk factors for AD?

Answer 2

-advancing age
-risk genes/family history of dementia
- previous head trauma (ex. football players often develop chronic trauma encephalopathy)
- low education level
- Down syndrome (3 copies of chromosome 21 means that they will make 50% more amyloid protein because they have way more amyloid precursor proteins).
-Diet and environmental factors (healthy diet and exercise can prevent AD).

Question 3

Late onset AD is at least ___ genetic

Answer 3

60%

Question 4

How did researchers study late onset AD?

Answer 4

They performed twin studies and looked at identical twins vs. fraternal twins to see their chances of developing AD.
They found genes that increased the chances of AD but still don’t guarantee it.
AD is a polygenic disorder: multiple genes interact to influence disease risk.

Question 5

AD Neuropathology: Amyloid Plaques

Answer 5

40-42 amino acid amyloid peptide

Question 6

AD Neuropathology: Neurofibrillary Tangles

Answer 6

hyperphosphorylated tau (occurs within neurons themselves).

Question 7

AD Neuropathology: Inflammation

Answer 7

reactive microglia and astrocytes

Question 8

Neuronal and Synaptic loss

Answer 8

driven by all the factors mentioned previously.

Question 9

What is the best correlate to the severity of dementia in AD?

Answer 9

Synapse loss

Question 10

What is the biggest cause of dementia?

Answer 10

AD

Question 11

Describe the tau protein

Answer 11

-Stabilizes microtubules in neurons (microtubules are part of neuron cytoskeleton and serve as a transport highway along axons and dendrites for important cargo).
-Very important for axon and dendrite remodeling involved in forming and storing memories.

Question 12

Alpha Beta is cleaved from a larger protein: ______

Answer 12

Amyloid precursor protein (APP)

Question 13

Most mutations ___ alpha beta cleave making more ____

Answer 13

1) increase
2) beta amyloid
Late onset

Question 14

How many cases are dominant early onset?

Answer 14

Around 2-3%

Question 15

Rare (2-3%) dominantly inherited forms of early onset AD are caused by mutations in the ___ or ____

Answer 15

1) APP
2) Presenillin (gamma secretase)
These mutations increase the generation of all Alpha Beta or specifically the more toxic Alpha Beta 42.

Question 16

But most AD cases are ____ around ____

Answer 16

Late onset
97%

Question 17

What is the amyloid cascade hypothesis?

Answer 17

Predicts that Alpha Beta accumulation is the initiating trigger for sporadic and familiar AD.
-Overproduction
-Mismetabolism
-Failure in clearance mechanisms.
Most compelling evidence emerged from understanding the molecular biology of genes that cause or increase susceptibility for AD.

Question 18

Have drugs that reduce Alpha beta amyloid worked in human clinical trials?

Answer 18

No!
Only just in 2022 and 2023 were 2 drugs that reduce Alpha beta approved for clinical use
(lecanemab and another one).
These drugs still aren’t that effective because only a tiny amount can get past the blood brain barrier.

Question 19

Beta amyloid pathology accumulates for ____ years before clinical symptoms begin.

Answer 19

10-15 years

Question 20

Why are Alpha Beta targeted therapies likely not working?

Answer 20

This is because it’s too little too late, the neural stem cells may be able to provide very minor effects. Amyloid accumulates 20 years before symptoms. So it is too late to do as much now.

Question 21

How do scientists model AD?

Answer 21

Mutant APP or PS genes: inject disease associated human genes into a mouse oocyte
“Transgenic mouse model”
3xTg-AD mice (created at UCI) develop both Alpha Beta and Tau pathologies.
3xTg-AD mice also develop age-related impairments in memory (The Morris Water Maze).

Question 22

Can neural stem cell transplantation affect pathology or memory in a mouse model of AD?

Answer 22

Yes,
neural stem cells improve learning in aged AD transgenic mice.
NSCs engraft and migrate throughout the hippomcapus.
Most NSCs differentiate into astrocytes or oligodendrocytes.
Only small number of GFP+ neurons are detected.

Question 23

How does NSC transplantation NOT improve cognition in 3xTg-AD mice? (What isn’t the reason for improvements?)

Answer 23

• Probably not by making new neurons
• not by altering alpha beta or tau pathology

Question 24

What is the reason for improvements in cognition in 3xTg-AD mice?

Answer 24

NSCs increase synapses in the hippocampus.
This increases BDNF
This increases synapses
This increases cognition.

Question 25

Do NSCs affect AD pathology?

Answer 25

NSC transplantation has no effect on alpha beta pathology or tau pathology

Question 26

What are neurotrophins?

Answer 26

They’re a group of proteins that promote growth and synapse formation.
Their levels are decreased in AD and PD.

Question 27

NSCs elevate levels of ______ within the brain

Answer 27

brain derived neurotrophic factor (BDNF) within the brain.

Question 28

IS NSC derived BDNF necessary for improved memory?

Answer 28

BDNF-depleted NSCs fail to improve cognition and a diminished effect on synaptic density.
When tested in an “ loss of function” experiment.