ECON 546 Lecture Notes - Lecture 21: Neurodegeneration, Kinesin, Tauopathy
27 Jun 2018
School
Department
Course
Professor
Lecture 21: Alzheimer’s Disease II Wednesday March 28, 2018
Dr. Hemant Paudel
Plaques Are Formed from the AB Peptide
- Large precursor protein (APP) cleaved from gamma and beta secretases
- Cleaved portion accumulates and forms the plaque
- Cleaved portion is a monomer, turns into oligomer, then fibrillary, then plaque
AB Homeostasis
- For peptides to cross the BBB, they need a protein carrier
- ApoE is a carrier protein that binds to AB and brings it out of the CNS (gets rid of it)
- Macrophages (microglia) are also responsible for degradation
Amyloid Cascade Hypothesis
- Theory about how APP is the start of a cascade that results in dementia as a pathology
What Is Alzheimer’s Disease?
- Alzheimer’s contributes to about 70% of dementia cases
Neuropathological Features
- Plaques, tangles, loss of neuronal functions, neuronal atrophy, loss of synapses
Loss of Synapses Correlates with Dementia
- Memory performance declines as the number of synapses fall
Synaptic Proteins in Dementia Treatment
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- In AD, areas of brain tissue are damaged and some messages do not transmit because of
the loss of synapses
Synaptic alternation in a Mouse Model of AD
- Under electron microscopy, it is possible to count the number of neurons and synapses
- There is a clear loss of synapses in a mouse model of AD
AB Peptide is Regarded as Central to AD
- Is AB the primary cause of neuronal disruption?
- Is it an interference with connection or transmission?
Proposed Mechanisms by Which AB Peptides Cause Dementia
- AB disrupts communication between neurons
oGlutamate is the major NT in excitatory synapses
oNMDAR is the calcium channel glutamate receptor
oAB oligomer can interact with NMDAR and enhances calcium release
oHigh calcium is extremely toxic
oHypothesis: AB binds with NMDAR and causes calcium toxicity leading to
neuronal dysfunction
- AB peptide causes synapse loss
oActin is the major cytoskeletal protein in dendritic spines
oThere is a clear loss of dendritic spines in AD
oAB peptide causes loss of actin cytoskeleton leads to spine loss
Neurofibrillary Pathology of AD – Tau Pathology
- Tau inclusions correlate with AD pathology
- Tau is a microtubule binding protein
- Abnormally phosphorylated in AD and related tauopathies
- Major component of the paired helical filaments
- Loss of tau function due to abnormal tau hyperphosphorylation is a characteristic
pathological feature of AD
- Reducing or preventing tau hyperphosphorylation is one of the current therapeutic
strategies against AD
Characteristic Features of PHF-Tau
- Abnormally phosphorylated
- Highly insoluble
- Functionally inactive
- Retarded mobility on a SDS gel
- Upon dephosphorylation:
oMigrates as a normal tau on SDS gel
oBecomes functionally active
Stages of NFT Pathology
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Document Summary
Large precursor protein (app) cleaved from gamma and beta secretases. Cleaved portion is a monomer, turns into oligomer, then fibrillary, then plaque. For peptides to cross the bbb, they need a protein carrier. Apoe is a carrier protein that binds to ab and brings it out of the cns (gets rid of it) Macrophages (microglia) are also responsible for degradation. Theory about how app is the start of a cascade that results in dementia as a pathology. Alzheimer"s contributes to about 70% of dementia cases. Plaques, tangles, loss of neuronal functions, neuronal atrophy, loss of synapses. Memory performance declines as the number of synapses fall. In ad, areas of brain tissue are damaged and some messages do not transmit because of the loss of synapses. Synaptic alternation in a mouse model of ad. Under electron microscopy, it is possible to count the number of neurons and synapses. There is a clear loss of synapses in a mouse model of ad.
