HD, Memory, & AD

Question 1

What are the early and late symptoms of HD?

Answer 1

Early: chorea, depression, irritability, remembering a fact, decision making, rapid jerky motions
Late: concentration problems, trouble eating & swallowing

Question 2

What is the cause of HD?

Answer 2

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

Question 3

What is anticipation?

Answer 3

expansion of CAG repeats in successive generation and this occurs when the gene is inherited from the father

Question 4

What is the pathology of HD?

Answer 4

Stiratal GABAergic neurons (MSNs) die. This leads to a decreased striatal volume

Question 5

In HD patients, what do the intranuclear inclusion bodies contain?

Answer 5

Contain aggregates of mutant HTT and other precipitated proteins

Question 6

What pathways does the degeneration of the MSNs in the striatum affect?

Answer 6

Decreased activity in the indirect pathway

Question 7

Why is the mutant protein the toxic component in HD?

Answer 7

If the mutant gene is untranslated, there will be no disease

Question 8

What role does BDNF play in HD?

Answer 8

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.

Question 9

Why does excitotoxcity happen in HD?

Answer 9

Extra-synaptic NMDARs have different subunits that allow a sustained influx of Ca2+ ions that cause more LTD and cell death

Question 10

What is the role of the proteostasis network in HD?

Answer 10

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.

Question 11

How does mHTT affect mitochondria?

Answer 11

HTT affects axonal transport of mitochondria, so in the presence of mHTT, there are less mitochondria at synapses.

Question 12

What does Tetrabenazine do for HD patients?

Answer 12

Inhibits VMAT2 loading of dopamine into synaptic vesicle

Question 13

What does plasticity mean?

Answer 13

Able to change the strength of a synapse in either direction

Question 14

What is the path of memory through the hippocampus?

Answer 14

Question 15

How does the increase in Ca2+ from the pre-synaptic membrane increase LTP?

Answer 15

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

Question 16

What are the mechanisms for long-lasting changes in synaptic transmission during LTP?

Answer 16

Transcription Factors activated when phosphorylated which increases transcription and gene expression leading to more AMPA receptors

Question 17

How does LTD occur in the hippocampus?

Answer 17

When the rate of Ca2+ ions coming into the cell decreases, phosphates are activated which decrease AMPA receptors on membrane

Question 18

What is declarative memory? What are these memories dependent on?

Answer 18

Episodic, history, words and their meanings. Hippocampus dependent

Question 19

What is nondeclaritive memory?

Answer 19

Motor skills, associations, puzzle solving skills

Question 20

What is Alzheimer’s disease?

Answer 20

AD is a progressive neurological disease of the brain with irreversible loss of neurons.

Question 21

What are the imaging hallmarks of FTD?

Answer 21

Atrophy of frontal, insular, & temporal lobes

Question 22

What are the imaging hallmarks of AD?

Answer 22

Atrophy of hippocampus, entorhinal cortex, & temporal lobe

Question 23

What are the imaging hallmarks of DLB?

Answer 23

Atrophy of parietal lobe

Question 24

How can the Pittsburgh compound be used to measure AD?

Answer 24

Pittsburgh compound that binds beta-sheet structures in beta-amyloid and PET scans show the location of the beta-amyloid

Question 25

What is the pathology of AD?

Answer 25

The pathology of AD shows extracellular beta-amyloid plaques and intracellular tangles of hyperphosphorylated tau in AD brains

Question 26

What are the beta-amyloid plaques composed of?

Answer 26

The plaques are composed of beta-amyloid peptide that are abnormally processed from a larger precursor APP protein

Question 27

What are neurofibrillary tangles?

Answer 27

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.

Question 28

How do plaques and tangles spread through the brain?

Answer 28

Plaques and tangles tend to spread through the cortex in a prion-like fashion.

Question 29

What are the vascular changes seen in AD?

Answer 29

Extensive AB deposits may impede clearance, compromise blood vessels, and affect the BBB.

Question 30

How does inflammation affect AD?

Answer 30

Amyloid deposits can activate astrocytes and microglia which release ROS that can activate apoptosis.

Question 31

What are the early-onset genetic mutations that lead to AD?

Answer 31

• 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

Question 32

What are the late-onset genetic mutations that lead to AD?

Answer 32

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

Question 33

What are the current drugs for AD? What do they do?

Answer 33

Memantine: NMDA receptor antagonist
NSAIDs: may alter where gamma-secretase cuts APP
Cholinesterase inhibitors: cholingeric neurons degenerate in AD