HD, Memory, & AD Flashcards
What are the early and late symptoms of HD?
Early: chorea, depression, irritability, remembering a fact, decision making, rapid jerky motions
Late: concentration problems, trouble eating & swallowing
What is the cause of HD?
Inherited monogenic disorder: tri-nucleotide repeat disease. The htt gene encodes HTT proteins, a CAG repeat in the htt gene causes extra glutamine in the protein
What is anticipation?
expansion of CAG repeats in successive generation and this occurs when the gene is inherited from the father
What is the pathology of HD?
Stiratal GABAergic neurons (MSNs) die. This leads to a decreased striatal volume
In HD patients, what do the intranuclear inclusion bodies contain?
Contain aggregates of mutant HTT and other precipitated proteins
What pathways does the degeneration of the MSNs in the striatum affect?
Decreased activity in the indirect pathway
Why is the mutant protein the toxic component in HD?
If the mutant gene is untranslated, there will be no disease
What role does BDNF play in HD?
In the presence of mHTT BDNF transcription goes down and and axonal transport does down leading to a loss of cortical neurons so less BDNF arrives at the MSN synapse which may affect the release of glutamate from the cortical neuron.
Why does excitotoxcity happen in HD?
Extra-synaptic NMDARs have different subunits that allow a sustained influx of Ca2+ ions that cause more LTD and cell death
What is the role of the proteostasis network in HD?
The presence of inclusion bodies in neurons in HD suggest that there is a defect in the proteasome system, maybe it is overwhelmed with misfolded mHTT.
How does mHTT affect mitochondria?
HTT affects axonal transport of mitochondria, so in the presence of mHTT, there are less mitochondria at synapses.
What does Tetrabenazine do for HD patients?
Inhibits VMAT2 loading of dopamine into synaptic vesicle
What does plasticity mean?
Able to change the strength of a synapse in either direction
What is the path of memory through the hippocampus?
How does the increase in Ca2+ from the pre-synaptic membrane increase LTP?
With more action, more Ca2+ goes in to stimulate kinases that will add more AMPA receptors to the membrane so there will be a bigger depolarization
What are the mechanisms for long-lasting changes in synaptic transmission during LTP?
Transcription Factors activated when phosphorylated which increases transcription and gene expression leading to more AMPA receptors
How does LTD occur in the hippocampus?
When the rate of Ca2+ ions coming into the cell decreases, phosphates are activated which decrease AMPA receptors on membrane
What is declarative memory? What are these memories dependent on?
Episodic, history, words and their meanings. Hippocampus dependent
What is nondeclaritive memory?
Motor skills, associations, puzzle solving skills
What is Alzheimer’s disease?
AD is a progressive neurological disease of the brain with irreversible loss of neurons.
What are the imaging hallmarks of FTD?
Atrophy of frontal, insular, & temporal lobes
What are the imaging hallmarks of AD?
Atrophy of hippocampus, entorhinal cortex, & temporal lobe
What are the imaging hallmarks of DLB?
Atrophy of parietal lobe
How can the Pittsburgh compound be used to measure AD?
Pittsburgh compound that binds beta-sheet structures in beta-amyloid and PET scans show the location of the beta-amyloid
What is the pathology of AD?
The pathology of AD shows extracellular beta-amyloid plaques and intracellular tangles of hyperphosphorylated tau in AD brains
What are the beta-amyloid plaques composed of?
The plaques are composed of beta-amyloid peptide that are abnormally processed from a larger precursor APP protein
What are neurofibrillary tangles?
Abnormally folded tau protein. In AD tau is hyperphosphorylated and polymerizes into paired helical filaments that form twisted strands. These tangles no longer bind to tubulin and therefore disrupt intracellular transport.
How do plaques and tangles spread through the brain?
Plaques and tangles tend to spread through the cortex in a prion-like fashion.
What are the vascular changes seen in AD?
Extensive AB deposits may impede clearance, compromise blood vessels, and affect the BBB.
How does inflammation affect AD?
Amyloid deposits can activate astrocytes and microglia which release ROS that can activate apoptosis.
What are the early-onset genetic mutations that lead to AD?
- APP is processed by secretases to make the beta-amyloid peptide. Mutations in APP lead to early-onset.
- PSEN 1&2 are components of the gamma-secretase activity that cleaves APP
What are the late-onset genetic mutations that lead to AD?
APOE is a major cholesterol carrier that supports lipid and protein transport and injury repair in the brain. Inheriting specific alleles of this gene can increase the likelihood of developing AD
What are the current drugs for AD? What do they do?
Memantine: NMDA receptor antagonist
NSAIDs: may alter where gamma-secretase cuts APP
Cholinesterase inhibitors: cholingeric neurons degenerate in AD
