Lecture 10: Alzheimer's Disease: Neural Stem Cells Flashcards
What is Alzheimer Disease (AD)?
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.
What are risk factors for AD?
-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).
Late onset AD is at least ___ genetic
60%
How did researchers study late onset AD?
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.
AD Neuropathology: Amyloid Plaques
40-42 amino acid amyloid peptide
AD Neuropathology: Neurofibrillary Tangles
hyperphosphorylated tau (occurs within neurons themselves).
AD Neuropathology: Inflammation
reactive microglia and astrocytes
Neuronal and Synaptic loss
driven by all the factors mentioned previously.
What is the best correlate to the severity of dementia in AD?
Synapse loss
What is the biggest cause of dementia?
AD
Describe the tau protein
-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.
Alpha Beta is cleaved from a larger protein: ______
Amyloid precursor protein (APP)
Most mutations ___ alpha beta cleave making more ____
1) increase
2) beta amyloid
Late onset
How many cases are dominant early onset?
Around 2-3%
Rare (2-3%) dominantly inherited forms of early onset AD are caused by mutations in the ___ or ____
1) APP
2) Presenillin (gamma secretase)
These mutations increase the generation of all Alpha Beta or specifically the more toxic Alpha Beta 42.
But most AD cases are ____ around ____
Late onset
97%
What is the amyloid cascade hypothesis?
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.
Have drugs that reduce Alpha beta amyloid worked in human clinical trials?
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.
Beta amyloid pathology accumulates for ____ years before clinical symptoms begin.
10-15 years
Why are Alpha Beta targeted therapies likely not working?
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.
How do scientists model AD?
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).
Can neural stem cell transplantation affect pathology or memory in a mouse model of AD?
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.
How does NSC transplantation NOT improve cognition in 3xTg-AD mice? (What isn’t the reason for improvements?)
- Probably not by making new neurons
- not by altering alpha beta or tau pathology
What is the reason for improvements in cognition in 3xTg-AD mice?
NSCs increase synapses in the hippocampus.
This increases BDNF
This increases synapses
This increases cognition.
Do NSCs affect AD pathology?
NSC transplantation has no effect on alpha beta pathology or tau pathology
What are neurotrophins?
They’re a group of proteins that promote growth and synapse formation.
Their levels are decreased in AD and PD.
NSCs elevate levels of ______ within the brain
brain derived neurotrophic factor (BDNF) within the brain.
IS NSC derived BDNF necessary for improved memory?
BDNF-depleted NSCs fail to improve cognition and a diminished effect on synaptic density.
When tested in an “ loss of function” experiment.
