Neurobiology of Neurodegenerative Disorders Flashcards
What are the 2 molecular “cardinal signs” of Alzheimer’s disease?
Amyloid beta (Aβ) plaques; Tau tangles
Describe the gross neuropathology of Alzheimer’s disease.
- Global atrophy: expanded sulci, shrunken gyri,
- Loss of white matter, even greater loss of grey matter
- Hippocampus greatly depleted
Most mutations responsible for genetic early-onset AD are found in which gene? Name the other genes in which mutations may cause this form of AD.
The Amyloid Precursor Protein (APP) gene, found on chromosome 21
Presenilin 1 (chr 14), Presinilin 2 (chr 1)
Describe the onset and prevalence of familial AD.
Early-onset - 30-70yrs old
Prevalence - very rare - so much so that individual mutations are named after places - e.g. Swedish: double mutation aa670-671 in APP
Some similarity to Down syndrome - trisomy 21
Describe the onset and prevalence of sporadic AD.
Onset - age > 65yrs
Prevalence - 5% over 65, 40% over 80
Although not a genetic disease, risk of developing sporadic AD is strongly associated with one gene. Describe the gene and the alleles involved.
ApoE (chr 19) - plasma cholesterol transport protein
Associated with sporadic, late-onset AD (LOAD)
Alleles - E2, E3, E4
Normal E4 frequency: 0.14
Frequency in LOAD patients: 0.50
E2 is protective, E4 is a risk factor
What is amyloidopathy, which is seen in AD?
- Senile plaques - extracellular deposits of Aβ fibrils - also found in Down syndrome teenagers.
- Endogenous membrane protein: APP.
Describe the processes involved in Aβ40 and Aβ42 formation.
- Aβ is cleaved from APP by secretase enzymes - α, β and γ
- α-secretase normally cleaves APP to form α-CTF
- β-secretase (BACE) cleaves APP to form β-CTF
- γ-secretase produces Aβ40 and Aβ42 from β-CTF - so only after β-secretase cleaves APP
- Presenilins are essential co-factors within the γ-secretase
- Aβ40 and Aβ42 aggregate into plaques
What is Pittsburgh compound B and what is its relevance to AD?
Pittsburgh compound B (PIB) binds to amyloid plaques, indicating the extent of damage to the brain when detected on a PET scan.
The scan also indicates which areas of the brain are most affected, and also the effectiveness of any treatment.
What is tauopathy?
- Neurofibrillary tangles contain hyper-phosphorylated tau protein.
- Microtubule filaments inside neurons in cerebral cortex.
- Note: some tau phosphorylation is normal - only excessive phosphorylation leads to tau tangles.
Explain why tau tangles cease neuronal function.
- Tau protein is crucial in forming the “railway track” microtubule filaments transporting molecules along an axon.
- Tau tangles cause loss of tau binding and microtubule dissociation, preventing the trafficking of molecules along the axon.
An 2000 experiment treated normal mouse neurons and tau deficient neurons with amyloid beta protein. What were the results, and what does this tell us?
- The normal mouse neurons were destroyed by the protein.
- The tau deficient cells remained normal.
- This indicates that tau hyperphosphorylation is a necessary prerequisite for amyloid beta toxicity.
- Amyloid beta causes tau to tangle.
What is cerebral amyloid angiopathy?
Aggregation of amyloid beta around small blood vessels in the brain
Name 4 drugs currently used in treatment of AD. What is the prognosis for AD with this treatment?
Cholinesterase inhibitors: donepezil, rivastigmine, galantamine
Memantine - NMDA receptor antagonist
Prognosis: cognitive decline is delayed by 6 months. These drugs offer purely symptomatic relief.
Describe briefly the 2 approaches to immunotherapy for AD treatment.
- Normal immunisation - injecting a small quantity of amyloid beta to trigger an immune response
- Passive immunity - injecting amyloid beta antibodies
