Alzheimer's disease Dr. Pond Flashcards
Which abnormalities are used to diagnose Alzheimer’s?
Neurofibrillary tangles
ß amyloid plaques (falsely porcessed proteins)
-> interfere with the ability of neurons to communicate with each other
Where do the Neurofibrillary tangles build up?
intracellular within the axons
-they are abnormally structured tau proteins -> become tangles
-tau proteins are important for microtubules that are responsible for the transport of molecules between the cell body and terminal axons
-> microtubule system becomes distructed
Which neurons are most susceptible to degradation in Alzheimer’s disease?
loss of cholinergic neurons in the septum and nucleus basalis -> they project to the cerebral cortex
-the cerebral cortex is important for short-term and long-term memory and memory storage
Drugs used in Alzheimer’s disease
-Acetylcholine esterase inhibitor (preserve ACh)
Acetylcholine esterase turns ACh into Acetyl and choline in the synaptic cleft
-Donepezil (Ericept) , rivastigmine, galantamine
ADE: N/V, diarrhea, loss of appetite
What are the protective effects of Amyloid precursor protein?
-inhibits NMDA receptors -> thereby preventing Ca influx - glutamatergic induced Ca influx (too much Ca will activate cell death cascade i nneurons)
-enhances glutamate transport acitity in the cleft -> glutamate removal in the snyapitc cleft - transport into glial cell and conversion into glutamine
-> too much glutamate can cause cell death
in Alzheimer APP is falsely processed and becomes ß amyloid
How do amyloids affect glutamate concentration in the synaptic cleft?
stimulates NMDA receptors -> more Ca influx -> cell death cascade activation
-inhibits glutamate transport into glial cells -> more glutamate available in the synaptic cleft -> which will stimulate NMDA receptors and finally Ca influx -> cell death through excitotoxicity
What is the role of NMDA receptors in a healthy brain?
NMDA receptors are important in the process of learning -> enhance synapses during learning
What type of receptors are NMDA receptors?
-ligate-gated ion channels: requires glutamate to bind
-voltage-gated: it requires sufficient depolarization for Mg2+ to be lifted
What is required to allow for Ca entry through NMDA receptors?
sufficient depolarization of the membrane -> achieved by AMPA receptors (Na channel)
the depolarization will lift the Mg blockage from the NMDA receptor -> Ca2+ influx (also Na+)
What is the consequence of the NMDA receptor being chronically exposed to Ca2+ influx?
-excitatory cell death of neurons
-the signal to noise ratio is impaired, so the cell is not able to specifically activate the synapse in a learning event
How does Memantine affect Ca influx
it is an NMDA antagonist
-blocks and prevents the chronic activation of NMDA receptors by ß amyloid
-still able to receive the signal in a learning event!, since memantine gets kicked off if enough glutamate is present
Targets of Memantine
-noncompetitive NMDA receptor antagonist
-5-HT3 antagonist
-weak nicotinic receptor antagonist
-can be used in combination with Anticholinesterase (Donepezil)
-> Namzaric (Donepezil, Namenda) for moderate Alzheimer’s disease
Which drugs target ß amyloids?
-monoclonal antibodies - mabs (different drugs target different parts of the ß amyloid)
-Aducanumab: removes ß amyloids from the brain
-Lecanemab: blocks the formation of the plaques
-Donanemab: targets ß amyloids that is found solely in plaques
What is the black box warning for monoclonal antibodies targeting ß amyloids?
amyloid-related imaging abnormalities (ARIA)
-> edema or microbleedins in the brain
other ADE: hives, hypersensitivity reactions, angioedema, headache
