Alzheimers disease

auguste deter

who was the first diagnosis of AD

forgetful, paranoia, difficulty answering questions, trouble with reading comprehension

symptoms associated with AD

decrease white matter, ventricular dilation, pronounced sulci

what are the gross anatomical changes associated with AD

synaptic density

researchers measure ___ ____ to quantify connection loss between neurons at the cellular level

25-30 %

what is the synaptic reduction in most cases

amyloid plaques

dense extracellular regions comprised of clusters or groupings of misfolded proteins

amyloid beta

amyloid plaques are composed of ____ ____, a peptide fragment derived from a larger protein

soluble oligomers

what are the most neurotoxic forms of amyloid plaques capable of damaging synapses and inhibiting long term potentiation

amyloid precursor protein

what is the origin of amyloid plaque

amyloid precursor protein

large transmembrane protein consisting of ~700 amino acids

non amyloidogenic pathway, amyloidogenic pathway

what are the two enzymatic pathways for processing APP

a-secretase

in the non amyloidogenic pathway, app is acted upon by ___

sAPP, CTF

in the non amyloidogenic pathway, a-secretase cuts APP within the AB sequence, effectively preventing the formation of the toxic AB peptide. The cleavage releases ___ and _____

sAPPa

a large soluble ectodomain released into the extracellular space

CTF

a carboxy-terminal fragment that remains in the membrane

p3, AICD

in the in the non amyloidogenic pathway, CTF is acted upon by y-secretase, releasing ___ and ____. this translocates to the nucleus to modulate gene expression

B secretase/BACE1

in the amyloidogenic pathway, app is acted upon by ___

sAPP b, CTF

in the amyloidogenic pathway, BACE1 acts on APP to release ___ and a different c terminal fragment ___

AB peptide

in the amyloidogenic pathway, CTF is acted upon by y secretase which results in release of ____

oligomers, fibrils, b pleated sheets

AB42 monomers very quickly aggregate into ____, which then form ___, eventually organizing into _____ that constitute the dense amyloid plaques

AB

at physiological levels, may help control excitatory signaling, maintaining the balance between inhibition and excitation necessary for brain activity. an imbalance between production and clearance leads to pathological accumulation

Neprilysin and insulin degrading enzyme

what are the two key enzymes responsible for breaking down AB

AB, insulin

IDE is responsible for degrading both ___ and ___

type 3 diabetes

If an individual develops type 2 diabetes, the body compensates by producing more insulin. because IDE must break down this excess insulin, it becomes occupied and is less available to break down AB. because of this, AD has been proposed as a form of ___

cytoskeleton

provides structure and acts as a transport system for the cell

actin filaments, intermediate filaments, microtubules

what is the cytoskeleton composed of

tau

microtubules rely on a soluble protein called ____ to bind them together and promote their assembly and stability

hyperphosphorylation

what causes tau to go from healthy to pathological tangles

the rubber band effect

when the tyrosine, serine, and threonine residues on tau become hyper phosphorylated and brittle and pulls away from the microtubules

helical filaments

once the hyperphosphorylated tau detatches from the microtubules, the tau molecules form insoluble twisted fibers called ____

neurofibrillary tangles

changes in plaques often scale up the formation of _____

age

what is the greatest risk factor of developing AD

amyloid cascade theory

the accumulation of AB peptides in the brain is the primary event in the pathogenesis of AD. This accumulation triggers a cascade of effects including neurotoxicity, synaptic failure, and the formation of neurofibrillary tangles

FAD

2% of AD cases are known as ____

APP that lead to enhance production of AB, presenilins increase the production of toxic AB

what are the mutations of in FAD

Avoid stress, control inflammation

what are the two strategies for primary prevention of AD

cortisol

patients with AD exhibit increased levels of ___ in both their blood and cerebrospinal fluid

increase AB levels

how does cortisol affect AB

loss of dendritic spines

how does stress affect dendrites

increase

how does stress affect a secretase

encephalitis and passive immunotherapy

what are the strategies for secondary prevention of AD

neural stem cell

what are the tertiary strategies of prevention