11 - Alzheimer's Disease II Flashcards
What is the difference between familial and sporadic Alzheimer's?
Why have many labs switched to modelling AD in rats, rather than mice? What does this suggest about AD?
Because rats show neurodegeneration associated with Ab buildup and mice don’t.
Accumulation of Ab plaque in human and mouse brain does not match with neurodegeneration. This may indicate that senile plaque build up is not the cause of neurodegeneration observed in AD
What shows the aggregates of Ab are toxic?
Small oligomers of Ab are responsible for neurotoxicity
- stimulate Tau phosphorylation and buildup of plaque
There are receptors that can interact with Ab and other proteins, what do these receptors do?
GM1 shown to induce oligomerization of Ab,
oligomers can have a variety of functions with
- NGF receptors, signalling apoptosis
- NMDA receptors, can cause oxidative stress and degeneration
- Insulin receptor leads to impairment of kinase and insulin receptor loss
- frizzled receptor (tau phosphorylation neurofibrillary tangles)
- Abnormal ion flow with pore formation
Overexpression of Ab stimulates GSK-3beta with Frizzled receptor, leading to what?
Tau neurofibrillary tangle formation
Ab can interact with glutamatergic receptors (NMDA and AMPA). What does this cause? How can this be blocked?
- Induced calcium release
- Apoptosis
Ab induced cell death can be blocked by NMDA and kainate receptors antagonists as well as apoptosis inhibitors
Ab oligomers induce Ca release in hippocampal slices and this effect can be blocked by either NMDA or kainate antagonists
What is APOE responsible for? (2)
- Transport of cholesterol
- Transport of Ab
Transports Ab into microglia, where it is degraded
Transports Ab into neurons, where it has host of intracellular effects
What do Apo-E knockout mice show
have highest Ab clear rate out of the brain
How can viruses be associated with AD? What is evidence for this?
Viral response or viral integration into the genome upstream of APOE gene.
Viral infections can interact with expression of ApoE
- Herpes simplex virus infection is more often found in AD patients (both familial and sporadic)
- Ab forms hours after viral infection (HSV)
- HPV requires an intramembrane protease γ-secretase
- HIV positive patients show increased Ab
True or false? Interaction with prion Protein (PrP) with Ab metalloprotein can cause pathogenesis in AD
True
How do we know Aβ and Tau peptides are mobile?
- Unilateral injection of Ab antibodies clears extracellular accumulation of Ab first in the ipsilateral hemisphere.
- Tau aggregates can propagate from the outside to the inside of a cell and from cell to cell
Describe intracellular Aβ
- APP produced in the golgi network is incorporated into the membrane
- Ab sequence is extracellular, but it can be internalized into endosomes
- Ab can accumulate in multivesicular bodies and lysosomes, as well as mitochondria, ER, golgi and cytosol
What can beta amyloid in the cytosol of cells affect?
Proteasome function
What can intracellular Ab that has aggregated into oligomers cause?
- Tau hyperphosphorylation
- Proteasome dysfunction
- Induce calcium and synaptic dysfunction
- Production of reactive oxygen species (ROS) in mitochondria
However, extracellular Ab prevails with age and AD progress.
Will reduction in plaque buildup from antibody treatment cause cognitive improvement in AD patients?
No, the plaque accumulation precedes significantly the onset of cognitive impairment
What is the evidence for soluble beta amyloid oligomers being responsible for Ab toxicity? (3)
Oligomeric Ab inhibits LTP in laboratory animals and impairs their performance in the water maze test.
- Aβ40 can inhibit formation of large oligomers of Aβ42, which seem to exhibit higher toxicity
- C-terminal fragments of Aβ were shown to inhibit Aβ42 toxicity in vitro
What type of treatment might be used for early prevention of Alzheimers in at risk populations (APP/presenilin mutations, Down syndrome etc.)?
Aβ Antibodies
What are possible mechanisms for extracellular Aβ oligomer induced toxicity? (4)
- Oligomeric Aβ can be produced in the presence of αB-crystallin, clusterin and ganglioside GM1.
- Oligomers induce apoptosis by binding to NGF receptor
- Neurotoxic effect of oligomers can be induced by binding with other receptors: NMDA, insulin, Frizzled, prion).
- Neurotoxic effect could also be from a change in ion balance by forming pores in the cell membrane
What is cellular prion protein (PrPc)? (4)
A cell surface glycoprotein that can act as an Aβ oligomer receptor to mediate synaptic dysfunction.
- The interaction between the Aβ oligomer and the prion does not require the infectious (misfolded) PrP conformation.
- Memory deficit induced by Aβ oligomers reduced by blocking receptor or knockout.
- Activation of NMDA receptor by binding with PrP, causing synaptic dysfunction
