Neurodegenerative Disorders Flashcards
Who taught this lecture?
Chris Rochet
What are the symptoms of Alzheimer’s?
- memory loss
2) impaired ability to learn, reason
3) impaired ability to carry out daily activities
4) anxiety, suspicion, hallucinations
Who first described AD?
Alois Alzheimer who’s patient was Auguste Deter
What are environmental risk factors of AD?
- Age
- Low educational level
- Reduced mental activity in late life
- Reduced physical activity in late life
5.Risks for vascular disease
6.Head injury
What do we physically see happen to the brain in AD?
brain shrinkage, senile plaques, and neurofibrillary tangles
What is brain shrinkage?
also known as atrophy, we see the brain get smaller with larger ventricular spaces. This is due to death of neurons
What is plaques and tangles?
Amyloid plaques are extracellular deposits of AB peptide. Neurofibrillary tangles are intracellular deposits of Tau.
Where might we see AD start?
entorhinal cortex
What is released from amyloid precursor protein (APP) and when?
B-secretase and gamma-secretase cleave amyloid precursor protein (APP). This releases amyloid-beta peptide (AB). AB peptide then start to aggregate and make amyloid plaques
What cells normally do to avoid AB being released?
They normally have a-secretase that cleaves the AB peptide, so it isn’t released
How many residues can AB peptide have? Why is this important?
AB can have 40 or 42 residues depending on gamma secretase cleavage location. AB-42 has a greater ability to aggregates. People who make AB-42 are likely to develop Alzheimer’s at a younger age
How does AB aggregate promote tau neuropathology?
- AB peptide starts to from oligomers which can form fibrils or can act on cell surface receptors
- Receptors activate kinases which phosphorylate tau.
- tau hyperphosphorylation will change its conformation, fall of microtubules, and form neurofibrillary tangle.
How does tangles lead to cytoskeletal defects and impaired axonal trafficking?
When tau falls off microtubules, the microtubules apart. The microtubules can no no longer act as tracts for axonal transport. The tangles clog up the network. This all leads to synaptic death.
How does AB aggregates cause neurotoxicity by triggering microglial activation and neuroinflammation.
- AB causes overactivation of microglial releases agents meant to kill a pathogen
- agent kill nearby neurons and as it dies it releases macromolecules
- causes activation of microglial
What is ApoE?
It is an LDL that is responsible for transporting cholesterol in brain; defects may increase AB deposition or reduce AB clearance
What are the three isoforms of ApoE?
ApoE2 - decreased risk of AD
ApoE3
ApoE4 - increased risk of AD
What are current AD therapies that only work short term?
Restore cholinergic neurotransmission using drugs that elevate levels of acetylcholine by inhibiting acetylcholinesterase
What do disease-modifying AD therapies try to do?
Amyloid therapies try to block or clear AB aggregation
Non-amyloid therapies block tau kinase
What is lecanemab?
It is a drug that clears AB. It is better for early stages of the disease
What makes early-diagnosis easier?
- F-Florabetapir (binds AB plaques)
- F-Flortaucipir (binds tau aggregates)
- blood tests to measure AB levels
What are Parkinson Disease symptoms?
A) Tremor at rest
B) Rigidity (muscle stiffness)
C) Akinesia/bradykinesia (slow movement)
D) Postural instability (impaired balance)
E) Mask-like appearance
F) speech difficulties
What is PD characterized by?
loss of dopamine neurons in the substantia nigra andloss of transmission through the nigrostriatal system
What percent of neurons are lost by the time patients show symptoms?
50% of nigral dopamine neurons or 70-80% of the nerve terminals in the striatum
What happens to the surviving neurons?
They have protein deposits called Lewy bodies enrich with clusters (aggregates) of the protein a-synuclein
What do patients with early-onset PD have a mutation in?
a-synuclein
What environmental toxins increase the risk of PD? Why?
Pesticides, herbicides, metals inhibit mitochondrial function
What is the aim of current PD therapies?
reestablish dopamine transmission by administrating L-DOPA so it can break down into dopamine
