4 Different Memory Systems
- Episodic memory
- Semantic memory
- Procedural memory
- Working memory
Specific episodes of your life, last minutes to years, explicit, declarative
Memory of facts, lasts minutes to years, explicit, declarative
Doing things, lasts minutes to years, explicit or implicit, nondeclarative
Short-term, lasts seconds to minutes, explicit, declarative
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
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)
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
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
Deficiency of which neurotransmitter was originally thought to be the cause of Alzheimer's?
What brain area projects neurons that supply ACh to other brain areas?
Precursors to ACh?
Choline + Acetyl CoA
ACh has (ionotropic/metabotropic) receptors
ACh is chewed up in synapse by what enzyme?
Acetyl cholinesterase (AChE)
Two types of ACh receptors
- nictonic (nAChR): ionotropic
- muscarinic (mAChR): metabotropic
Agonist and antagonist of nAChR
- Agonist: nicotine
- Antagonist: curare
Agonist and antagonist of mAChR
- Agonist: muscarine
- Antagonist: Atropine
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
A common AChE inhibitor originally used to treat Alzheimer's; what happens in patients who use it?
- Improvement at first, but dementia is essentially delayed ~6-12 months
Donepezil pharmacokinetics: 1st order or Zero order?
Donepezil pharmacokinetics: Half-life
Donepezil pharmacokinetics: lipid solubility and VOD
Both very high
Donepezil pharmacokinetics: metabolism
Metabolized by liver P450 systems (2D6, 3A4)
How does liver failure affect donepezil pharmacokinetics?
Liver failure decreases clearance, increases plasma levels
How does renal failure affect donepezil pharmacokinetics?
Kidney doesn't clear the active drug, so kidney failure doesn't really affect it
Donepezil: age, gender, race effects
- Age: older = decreased clearance
- Gender: none
- Race: none
Glutamate: what is it?
- Amino acid
- Also can be an excitatory neurotransmitter; is the most common excitatory neurotransmitter in the brain
Glutamate uses (ionotropic/metabotropic) receptors
3 ionotropic glutamate receptors
All ionotropic gluatamate receptors conduct ________ ions. ________ receptors also conducts __________.
- NMDA also conducts calcium
Which ionotropic glutamate receptor directly activates a second-messenger system? How?
- Conducts calcium ions
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)
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
Memantine pharmacokinetics: Half life
Memantine pharmacokinetics: VOD
Memantine pharmacokinetics: Clearance
Cleared by kidney
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
Compound used to see beta-amyloid accumulation in brain
Concept of pre-symptomatic Alzheimer's disease
Stuff starts happening well before diagnosis