Module IV - Lecture 7 - Alzheimer's Disease Flashcards
What is AD?
cognitive dimunition and dementia and progresses rapidly
What is the affect of human life spans increasing?
more neurodegenerative diseases cause better at combatting cardiac diseases
What does normal age related memory loss cause?
nothing does not impair cognition - harder to form explicit declarative memories
What is mild cognitive impairment?
gradual and modest loss of cognitive abilties
What is dementia?
severe accelerating loss of cognition
What is the distinction between mild cognitive impairment and dementia?
it inly shows after the initial decline in cognitive performance
What is age related cognitive decline specific to and what types of memory is it selective for?
specific to individuals
affects working and long term memory but not vocabulary
What are age dependent changes in brain structure?
-this decline is associated with shrinking cortical structures and ventricular enlargement - more narrow gyri (bumps) and wider sulci (depression)
What are age dependent changes in synapse number?
there are reduction in neuropil which are axons, dendrites, and spine
-number of glutamatergic synapses decreases with age (have a period of rapid generation and peaks ate adolescence then pruning and this decreases with age so if you lose these synapses you loose this information)
What are symptoms of Alzheimers disease?
-memory loss
-vocab issues
-problems in speaking and reading and writing and comprehension
-disorientation time and place
-poor judgment
-problems with abstract thinking
-misplacing things
-drastic personality change
-difficulty performing familiar tasks/ routine chores
What happens with the number of elderly people increasing and the incidence of AD and why?
incidence of AD is increasing
-get AD at 70 affects one in eight people above 65
-number of people with AD will triple in next 25 years
How does brain structure change with AD?
brain is atrophies narrwo gyri wide sulci less brain weight bigger ventricles and neurons dying
-neurdegenerative disease cause neurons die while they do not in age related cognitive decline
What is amyloid?
large aggregates of fibrillary peptides arranged as sheets and these surround swollen axons and dendrites an the neuronal processes are associated with the process of astrocytes and microglia
-blebbing of axons if swelling of it
What are neurofibrillary tangles?
neurons affected are still alive but have cytoskletal abnormalities and the tangles are filamentous inclusions int he cell bodies proximal dendrites and axons that contains paired helical fragments and 15nm straight filaments
How are neurofibrillary tangles made?
hyperphosphorylation of tau causing it to aggregate or group in an insoluble form
What is tau?
protein that helps MT alpha and beta tubulin stick together and when they are hyperphosphorylated they stick together instead of with the tubules causing these neurofibrillary tangles
Where are neurofibrillary tangles and amyloid plaques found in the brain?
entorhinal area, hippocampus, nucleus basalis, neocortex
What areas are implicated in declarative memory issues in AD?
entorhinal area, hippocampus
What areas are implicated in age related cognitve decline in normal subjects?
frontostriatal circuits
Does AD have widespread neuronal death and what does that show along with the areas of the brain it affects?
yes, it is not related to age related cognitive decline cause it has neuronal death and affects different brain regions
What causes formation of amyloid plaques?
amyloid precursor protein or APP is a large TM glycoprotein that is in dendrites cell bdoies and axons in neuorns and noneuronal cells and beta secretase iand gamma secretase presenilin n neuronal cells cleave APP and creates ABeta peptide prone to aggregation
-in noneuronal cells alpha secretase cleaves APP in the middle of the ABeta sequence and prevents formation of the ABeta peptide and helps explain why ABeta peptides are largely confined to the nervous system
If you KO APP in an animal what can you have?
some deficits but are not impaired in any ay and may affect LTP in small way but nothing serious
What is concordance rate of AD?
MZ (75%) DZ(26%)
-very strong genetic component
Why do most people with down syndrome get AD?
APP gene on 21st chromosome so people with down syndorme have three copies of 21st chromosome and make too much APP and this predisposes to AD - 60% more likely to get while other peopple have 10% chance
What other mutations are linked with AD?
APP gene
PS1 which is gamma secretase which cleaves APP into two subunit PS1 and PS2 and these two enzyme can cause gamma secretase to leave more APP and make more ABeta peptides
What does excess ABeta do?
these plaques poison neyrons and cause synaptic dysfunction and degenartion of axon terminals and neuronal death
-aggregation of these plaques is the bodies abilties to sequester toxic protein fragments meaning these fragments bind to synaptic proteins and affect trafficking of GluRs and impeded LTP and cause memory deficits and loss of dynases
-this means the plaques are not the problem the fragments are
Loss of what is strongly correlated with cognitive decline in AD?
glutamatergic synapses
What is neuronal death in AD preceded by?
loss of Glu synapses - lose synapses before plaque formation - and as disease progresses lose higher neurons
Have mutations in tau gene been lead to be found in familai AD and what does this mean?
no; neurofibrillary tangles are a consequence or correalte of AD
What is seen in a variety of ND disorders
filamentous deposts of hyperphosphorylated tau
Mutations in tau gene have been found to underlie what disease?
frontotemproal dementia PD type 17 - related to AD but has no plaques
What do symptoms of AD better correlate with and where in the brain was this seen?
number and distrbution of tangles than plaques in entorhinal cortex
Are both ABeta and tau involved in AD and how do we know this?
yes because both mutan APP and tau in transgenic mice have mroe sevre AD deficits than overpexression of ither alone
How was the interplay of plaques and tangles found?
-inject Abeta42 into region of mouse with mutant tau causes more tangles in nearby neurons
-reduce number of plaques get less levels of hyperphosphorylated tau
-means tau does not cause AD but plays a role in disease progression
What genes determine if you are at risk for AD?
ApoE genes - they are cholesterol and lipid carriers
-have three alleles ApoE2, ApoE3, ApoE4
-ApoE4 is at risk for AD - 40-50% of pop of AD have this gene 2 ApoE4 genes 91% chance of AD
What do we think is the role of ApoE4 in AD?
bidns to ApoE receptor with greater affinity than ApoE2 and ApoE3 which causes signal transduction cascade and causes elevation and transcription of APP gene and this regulates how much ABeta is made cause more APP is produced
What are some advances in diagnosing AD?
PET - visualize amyloid plaques by using compound which bind to amyloid
What is a compound that bidn to ABeta with high affinity?
Pittsburgh compound B and radiactuvely labeles carbon or fluorine is detected by PET
-helps determine stage of disease and distinguish between age releated cognitive decline and AD
What are some directions of research in treating AD?
-inhibits beta and gamma secretase activity - these enzymes cleave other proteins thouht an fthis could cause unwanted side effects such as productin of T and B cells
(NEED TO FIND DRUG THAT BINDS TO CLEAVAGE SITE ON APP)
-increase alpha secretase activty
-block APoE4 action by converting it to APoE3 via amino acid change whcih is protective - this is hard because viral integration of DNA other genes can mess with other proteins
What is ABeta immunotherapy?
immunize with ABeta so make antibodies against it to reduce plaques - improve cognition in mice
What is an injectable antibody against ABeta?
lacanemab - failed phase 3 clinical trial
