Module IV - Lecture 7 - Alzheimer's Disease

Question 1

What is AD?

Answer 1

cognitive dimunition and dementia and progresses rapidly

Question 2

What is the affect of human life spans increasing?

Answer 2

more neurodegenerative diseases cause better at combatting cardiac diseases

Question 3

What does normal age related memory loss cause?

Answer 3

nothing does not impair cognition - harder to form explicit declarative memories

Question 4

What is mild cognitive impairment?

Answer 4

gradual and modest loss of cognitive abilties

Question 5

What is dementia?

Answer 5

severe accelerating loss of cognition

Question 6

What is the distinction between mild cognitive impairment and dementia?

Answer 6

it inly shows after the initial decline in cognitive performance

Question 7

What is age related cognitive decline specific to and what types of memory is it selective for?

Answer 7

specific to individuals
affects working and long term memory but not vocabulary

Question 8

What are age dependent changes in brain structure?

Answer 8

-this decline is associated with shrinking cortical structures and ventricular enlargement - more narrow gyri (bumps) and wider sulci (depression)

Question 9

What are age dependent changes in synapse number?

Answer 9

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)

Question 10

What are symptoms of Alzheimers disease?

Answer 10

-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

Question 11

What happens with the number of elderly people increasing and the incidence of AD and why?

Answer 11

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

Question 12

How does brain structure change with AD?

Answer 12

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

Question 13

What is amyloid?

Answer 13

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

Question 14

What are neurofibrillary tangles?

Answer 14

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

Question 15

How are neurofibrillary tangles made?

Answer 15

hyperphosphorylation of tau causing it to aggregate or group in an insoluble form

Question 16

What is tau?

Answer 16

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

Question 17

Where are neurofibrillary tangles and amyloid plaques found in the brain?

Answer 17

entorhinal area, hippocampus, nucleus basalis, neocortex

Question 18

What areas are implicated in declarative memory issues in AD?

Answer 18

entorhinal area, hippocampus

Question 19

What areas are implicated in age related cognitve decline in normal subjects?

Answer 19

frontostriatal circuits

Question 20

Does AD have widespread neuronal death and what does that show along with the areas of the brain it affects?

Answer 20

yes, it is not related to age related cognitive decline cause it has neuronal death and affects different brain regions

Question 21

What causes formation of amyloid plaques?

Answer 21

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

Question 22

If you KO APP in an animal what can you have?

Answer 22

some deficits but are not impaired in any ay and may affect LTP in small way but nothing serious

Question 23

What is concordance rate of AD?

Answer 23

MZ (75%) DZ(26%)
-very strong genetic component

Question 24

Why do most people with down syndrome get AD?

Answer 24

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

Question 25

What other mutations are linked with AD?

Answer 25

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

Question 26

What does excess ABeta do?

Answer 26

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

Question 27

Loss of what is strongly correlated with cognitive decline in AD?

Answer 27

glutamatergic synapses

Question 28

What is neuronal death in AD preceded by?

Answer 28

loss of Glu synapses - lose synapses before plaque formation - and as disease progresses lose higher neurons

Question 29

Have mutations in tau gene been lead to be found in familai AD and what does this mean?

Answer 29

no; neurofibrillary tangles are a consequence or correalte of AD

Question 30

What is seen in a variety of ND disorders

Answer 30

filamentous deposts of hyperphosphorylated tau

Question 31

Mutations in tau gene have been found to underlie what disease?

Answer 31

frontotemproal dementia PD type 17 - related to AD but has no plaques

Question 32

What do symptoms of AD better correlate with and where in the brain was this seen?

Answer 32

number and distrbution of tangles than plaques in entorhinal cortex

Question 33

Are both ABeta and tau involved in AD and how do we know this?

Answer 33

yes because both mutan APP and tau in transgenic mice have mroe sevre AD deficits than overpexression of ither alone

Question 34

How was the interplay of plaques and tangles found?

Answer 34

-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

Question 35

What genes determine if you are at risk for AD?

Answer 35

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

Question 36

What do we think is the role of ApoE4 in AD?

Answer 36

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

Question 37

What are some advances in diagnosing AD?

Answer 37

PET - visualize amyloid plaques by using compound which bind to amyloid

Question 38

What is a compound that bidn to ABeta with high affinity?

Answer 38

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

Question 39

What are some directions of research in treating AD?

Answer 39

-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

Question 40

What is ABeta immunotherapy?

Answer 40

immunize with ABeta so make antibodies against it to reduce plaques - improve cognition in mice

Question 41

What is an injectable antibody against ABeta?

Answer 41

lacanemab - failed phase 3 clinical trial