Alzhimers disease Flashcards
what are key cellular differences between normal and Alzheimer’s brain?
-extensive neuronal cell death
-amyloid plaques and neurofibrillary tangles
what regions of the brain are impacted?
-neocortex (sensory, perception, cognition, etc)
-hippocampus (memory)
-amygdala (emotions)
-entorhinal cortex
what are neuritic plaques composed of?
small fragment of trans-membrane protein amyloid precursor protein (APP)
what are neurofibrillary tangles composed of?
an abnormal form of tau
what are the 2 classes of Alzheimer’s disease?
-sporadic (not inherited)
-familial (inherited)
what are mutations that cause Alzheimers?
-APP
-Presenilin-1
-Presenilin-2
mutations in Tau gene cause closely related dementias
autosomal dominant mutations
ApoE allele
major influence on sporatic (ApoE2, ApoE3, ApoE4)
-recent effort to have ApoE4 as cause
-ApoE4 doesn’t inhibit lambda-secretase, allowing more beta-amyloid to be made
APP
transmembrane protein
-resides in plasma membrane
-highly expressed in synapses
lambda and beta secretase
cut protein within lipid bilayer
-results in beta-amyloid plaque
-increased APP mutations increase beta-secretase cleavage
-increase PSEN1/2 increase lambda-secretase activity
beta-amyloid plaques clearance (normal vs AD)
normal: beta-amyloid plaque clearance is equal to generation of it
AD: 30% reduction in beta-amyloid clearance
what kind of building block is toxic?
oligomers of beta-amyloid plaques
-polymers aren’t toxic
why do oligomers cause neuronal cell death?
-forming unregulated calcium ion channels
-JNK activation, Bcl downregulation
-promoting tau dysfunction
what is the function of tau
-copurifies and binds directly to MT
-suppresses MT dynamics
-initiate axon outgrowth
what are neurodegenerative diseases that exhibit abundant tau-positive filamentous lesions
-AD
-corticobasal degeneration
-FTDP-17
-Picks disease
-progressive supranuclear palsy
genetic linkage of Tau to FTDP-17, PSP, Picks, and CBD
-neuronal cell death and abnormal tau fibers
-no amyloid plaques
tau alternative splicing
fetal: 100% 3 repeat tau (doesnt stabilize MT as well)
adult: 50% 3 repeat, 50% 4 repeat (promote stability of MT) (disease=75% 4, 25% 3)
is there a pathological relationship btwn beta-amyloid plaques and tau?
tau is required for beta-amyloid mediated death
-tau is downstream of beta-amyloid
neuronal cell death pathway with APP and tau?
beta-amyloid induced neuronal cell death is tau dependent
hyperphosphorylation of tau
in neurofibrillary tangles
-believed to be key to tau disfunction in AD
how might alterations in tau action cause neurodegeneration?
Tau dissociation->NFT formation->GOF=cell death
or
aberrant MT dynamics (over/under stabilization)->LOF MT function->cell death good evidence
what goes wrong if tau isn’t working properly?
MT aren’t built/stabilized properly
-axonal transport is compromised
epothilone D
blood brain barrier permanent MT stabilizing drug used in cancer chemo
-lipiphilic to get across blood brain barrier
how is nervous impacted by bad Tau
it is transported along pathway throughout nervous system
-with time, bad Tau increases and good tau decreases
how does tau go from cell to cell?
transported via exomes
what is used to treat AD
-acetylcholinesterase inhibitors (mild, moderate AD), treats symptoms
AD vaccine
-inject mice with beta-amyloid, causing immune response->antibodies
-results: mice get fewer and smaller amyloid plaques
-resulted in high levels of neuro-inflammation
what is one of the main concerns the AD vaccine?
getting past the blood brain barrier
-a lot of anti beta-amyloid, some could get across barrier and reduce amount of beta-amyloid in brain
drugs that inhibit beta- and lambda-secretase
drugs failed with massive side effects
what about drugs being administered too late?
-molecular pathology is underway long before first clinical symptoms
-some of the drugs are failing bc they are administered too late
passive immunization
make monoclonal Ab against beta-amyloid plaques and infuse into patients
anti beta-amyloid plaque monoclonal Ab
-aducanumab: controversially approved by FDA
-donanemab: slowed cognitive decline, effective for modterate levels of pathological tau (FDA approved)->targets plaque
-lecanemab: slowed cognitive decline (FDA approved)->targets oligomers
