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4 Different Memory Systems
- Episodic memory
- Semantic memory
- Procedural memory
- Working memory
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Episodic memory
Specific episodes of your life, last minutes to years, explicit, declarative
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Semantic memory
Memory of facts, lasts minutes to years, explicit, declarative
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Procedural memory
Doing things, lasts minutes to years, explicit or implicit, nondeclarative
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Working memory
Short-term, lasts seconds to minutes, explicit, declarative
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Amyloid plaques vs. neurofibrilary fibers
- Amyloid plaques: outside cell, made of accumulations of beta-amyloid that stick together
- Neurofibrilary fibers: inside cell, made of hyperphosphorylated tau that stick together
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Amyloid mechanism and cascade (lots of stuff)
- Amyloid Precursor Protein (APP) is a normal protein
- 3 enzymes degrade it - alpha, beta, and gamma secretase
- If alpha doesn't help chew up APP and only beta and gamma do, then beta-amyloid is produced
- Beta-amyloid accumulates, forms plaques which become malignant and leads to cell death (among other things)
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To help treat Alzheimer's, it may be good to (increase/decrease) alpha secretase, (increase/decrease) beta secretase, or (increase/decrease) gamma secretase?
- Increase alpha
- Decrease beta
- Decrease gamma
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Default Network: What is it, how is it related to Alzheimer's?
- Brain network that's active when you're not paying attention to outside world (like daydreaming)
- Many of these areas are the same areas that show high levels of beta-amyloid accumulation in Alzheimer's
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Deficiency of which neurotransmitter was originally thought to be the cause of Alzheimer's?
ACh
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What brain area projects neurons that supply ACh to other brain areas?
Nucleus basalis
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Precursors to ACh?
Choline + Acetyl CoA
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ACh has (ionotropic/metabotropic) receptors
Both
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ACh is chewed up in synapse by what enzyme?
Acetyl cholinesterase (AChE)
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Two types of ACh receptors
- nictonic (nAChR): ionotropic
- muscarinic (mAChR): metabotropic
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Agonist and antagonist of nAChR
- Agonist: nicotine
- Antagonist: curare
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Agonist and antagonist of mAChR
- Agonist: muscarine
- Antagonist: Atropine
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How to increase ACh levels: what can we do, what can we not do?
- Can't: block reuptake, since ACh isn't reuptaken
- Can: inhibit AChE, which chews up ACh in synapse
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A common AChE inhibitor originally used to treat Alzheimer's; what happens in patients who use it?
- Donepezil
- Improvement at first, but dementia is essentially delayed ~6-12 months
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Donepezil pharmacokinetics: 1st order or Zero order?
1st order
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Donepezil pharmacokinetics: Half-life
70 hours
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Donepezil pharmacokinetics: lipid solubility and VOD
Both very high
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Donepezil pharmacokinetics: metabolism
Metabolized by liver P450 systems (2D6, 3A4)
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How does liver failure affect donepezil pharmacokinetics?
Liver failure decreases clearance, increases plasma levels
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How does renal failure affect donepezil pharmacokinetics?
Kidney doesn't clear the active drug, so kidney failure doesn't really affect it
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Donepezil: age, gender, race effects
- Age: older = decreased clearance
- Gender: none
- Race: none
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Glutamate: what is it?
- Amino acid
- Also can be an excitatory neurotransmitter; is the most common excitatory neurotransmitter in the brain
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Glutamate uses (ionotropic/metabotropic) receptors
Both
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3 ionotropic glutamate receptors
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All ionotropic gluatamate receptors conduct ________ ions. ________ receptors also conducts __________.
- Sodium
- NMDA also conducts calcium
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Which ionotropic glutamate receptor directly activates a second-messenger system? How?
- NMDA
- Conducts calcium ions
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Special characteristics of NMDA receptors (4)
- Conduct calcium ions and activate second-messenger systems
- Require glycine or D-serine to be bound to a second site
- Magnesium ions block conductance until membrane becomes depolarized (from some other excitatory receptor)
- Non-competitive antagonism of PCP and memantine: PCP and memantine bind to a site in the channel and blocks it (non-competitive since they don't block glutamate binding)
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Memantine: What is it, what does it treat, and what is its mechanism of action?
- NMDA antagonist
- Moderate to severe Alzheimer's
- Non-competitive antagonism - binds to site inside channel to block it; doesn't affect glutamate binding
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Memantine pharmacokinetics: Half life
60-100 hours
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Memantine pharmacokinetics: VOD
High
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Memantine pharmacokinetics: Clearance
Cleared by kidney
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Effectiveness of memantine?
- Can help a little bit, only in moderate or severe Alzheimer's
- Doesn't work in mild Alzheimer's
- Not very effective; essentially delays dementia
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Compound used to see beta-amyloid accumulation in brain
PIB
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Concept of pre-symptomatic Alzheimer's disease
Stuff starts happening well before diagnosis
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