Ger 3 Alzheimer's Flashcards
What is the main RF for ALzheimer’s Disease?
AGE
How many new cases per 100,000 people after age 65?
1275
What does the incidence of disease do every 5 years after age 65?
DOUBLES
After age 85, what % of the population receives this diagnosis?
33%
What things are associated with aging, thus leading to AD?
- Oxidative stress
- Impaired folding function of the ER
- Impaired proteosome
What is the prognosis for most with Alzheimer’s disease?
For most, it is death within 3-9 years, depending on the severity and progression of the disease
What is the most common pathological finding of AD?
Most common finding is aggregated beta-amyloid deposits leading to plaques and dystrophic neurites in neocortical terminal fields…often thought that the imbalance between AB production and clearance leads to accumulation
What are truncated proteins due to?
Proteolysis of amyloid precursor protein by…
- Beta-site precursor protein-cleaving enzyme-1 (BACE-1)
- Beta-secretase
- Gamma secretase (contains presenilin-1…catalytic core)
* These 3 are in order
What are beta-amyloid deposits?
Natural products of metabolism and are between 36-43 AA in length
What do beta-amyloid proteins normally do at the synapse?
Dampen over-excited neurons
Which beta-amylod protein is more aggregation prone and damaging (toxic to cells)?
Beta-amyloid 42
Which beta-amyloid protein is more prevalent?
Beta-amyloid 40
With regards to beta-amyloid, what is thought to lead to disease state(AD)?
Over-production and lack of clearance is what is thought to lead to the disease state …oxidative stress, impaired folding function of the ER and impaired proteasome functioning are all associated with aging, thus leading to AD
What are 2 pathological forms that beta-amyloid can aggregate into?
- Fibrils –> Beta- pleated sheets –> Insoluble plaques
2. Monomers/oligomers –> Intermediate assemblies
Which pathological form of beta-amyloid is most toxic to synapses?
Monomers/Oligomers –> Intermediate assemblies
-The severity of cognitive effects is dependent on the concentration of soluble oligomers, no the overall beta-amyloid load
What 2 enzymes normally degrade beta-amyloid monomers and oligomers?
- Neopresilyn
- Insulin degrading enzyme
* Deficiencies in these enzymes may lead to accumulation of beta-amylod proteins
What is another pathological finding seen in AD?
Neurofibrillary tangles
Where are neurofibrillary tangles seen in AD?
Neo-temporal lobe structures (pyramidal neurons)
What are neutofibrillary tangles made of?
Hyper-phosphorylated Tau proteins
What is tau a normal constituent of?
Microtubules
Are neurofibrillary tangles specific for AD?
No… but they are a predictor in the severity of the disease
What does hyperphosphorylated Tau do in cells?
It is insoluble and will aggregate into paired helical structures and no longer associate with microtubules
In AD, are there mutations to Tau protein?
No, just aggregation into intermediate groups (In Parkinson Disease, there are mutations)
Are the intermediate aggregations of Tau cytotoxic?
Yes… (like beta-amyloid)
What tests might be good indicators for those with mild cognitive impairment?
T181 and T231
Which happens first…beta-amylod aggregation or Tau?
Beta-amyloid aauggregation precedes Tau
Does beta-amyloid induced degeneration of neurons require Tau?
YES
What is AD primarily a disease of?
Synaptic failure…hippocampal synapses begin to decline in patients with mild cognitive impairment
What are the 2 effects of beta-amyloid oligomers on the synapse?
- Decreases long term potentiation and dendritic spines while simultaneously increasing long term depression
- Pre-synaptic transmission is decreased as is post-synaptic glutamate receptor ion currents
What are glutamate receptor ion currents most likely lost due to?
Endocytosis of NMDA receptors and alpha-amino-5-hydroxy-5-methyl-5-isoxazole-propionic acid surface receptors
What does alpha-amino-5-hydroxy-5-methyl-5-isoxazole-propionic acid surface receptors down regulation cause?
Lasting synaptic inhibition despite excessively high stimulation
What do neurotrophins do?
Promote the proliferation differentiation and survival of neurons and glia…they are key in memory,learning, and behavior
What is seen in the cholinergic neurons of the forebrain of AD patients?
Heavily reduced neurotrophin receptors
What else is reduced in AD (shown in animal models with injection of beta-amyloid 42)?
Brain derived neurotropic factor
What receptors are up-regulated in early AD, but drop off sharply as the disease progresses?
Pre-synaptic alpha-7-nicotinic acetylcholine receptors
Why do cholinesterase inhibitors like rivastigmine work in AD?
Because beta-amyloid binds to the cholinergic receptors causing decreased transmission
What are 3 effects beta-amyloid has making it a potent mitochondrial poison?
- Damaging key enzymes in specific cells in the brain…most notably damaged is cytochrome C in the neural mitochondria
- Electron transport chain is damaged–> Energy loss within the cells
- Superoxide radicals in the mitochondria as well as cytochrome C damage can lead to apoptosis
What can hydrogen peroxide do?
Readily diffuse into the cytosol and participates in metal-ion catalyzed hydroxylated radical formation
What does peroxidation of membrane lipids to?
Creates toxic aldehydes and other essential cell proteins are oxidized directly causing carbonyl and nitrated derivatives
What do insulin signaling pathway disturbances lead to?
High fasting insulin levels and low rates of glucose disposal (cells are showing resistance
Why are glucose intolerance and Type 2 diabetes considered a RF for AD?
These conditions cause a depletion in the neural ability to generate adequate energy
What does high glucose result in?
- Damage to the hippocampus
- Upregulated Tau protein
- Depleted levels of insulin degrading enzyme (needed for depletion of beta-amyloid)
What perpetuates the cycle of protein aggregation in AD?
Vascular injury and parenchymal inflammation
What % of AD population is patients with vascular disease?
60-90% - The vast majority coming from those with major infarct
What % of patients with AD may be affected by cerebral amyloid angiopathy?
90%
What else is beta amyloid possibly cytotoxic to?
Vascular endothelium
What 2 things are very prevalent in fibrillar plaques?
- Microglia
2. Astrocytes
What do chronically activated microglia do?
Release pro-inflammatory cytokines (IL-1, IL-6, and TNF) ….after they engulf lots of beta-amyloid
What else might chronically activated microglia cause?
Activation of complement (inflammatory damage)
What does elevated cytosolic calcium lead to?
Aggregation of beta amyloid and amyloidogenesis
What does beta-amyloid form in relation to Ca?
Forms voltage independent cation channels in lipid membranes leading to Ca influx
What activates voltage-gated Ca channels leeading to excessive Ca?
Glutamate
What is the effect of derrangements in axonal transports?
Reduce the transmission of important axonal cargo to the nerve terminal
What proteins regulate the fast anterograde transmission of axonal cargo in vesicles?
Kinesin proteins along with Tau (cross bridge protein in microtubules)
What are products that undergo fast anterograde transmission to the termial fields that could be causative in amyloid protein derangement and deposition of beta-amyloid?
- BACE
- Presenilin-1
What is seen in AD with regards to aberrant cell re-entry?
Cells have difficulty suppressing the normal cell cycle (typically seen in entry from G1-S phases of mitosis
What is ApoE and what does it do?
- It is the primary cholesterol transporter in the brain (glial)
- It increases the uptake and incorporation of cholesterol into the membrane rafts
What does massive accumulation of cholesterol in the membrane of neural crest cells cause?
Assembly of secretases that create beta-amyloid
–>Without turnover of the lipid membrane (which doesn’t happen in a highly esterfied cholesterol membrane) production of beta-amyloid outweight celarance…HYPOTHESIS
What factor is the risk increased by with ApoE4?
19… this leads to increased beta-amyloid deposition
What is the largest risk factor for the progression of AD?
AGE
What are other factors that increase risk for progression to AD?
- Mutation in the presenilin gene
- Glucose intolerance and Type II Diabetes
- Those with vascular diseases
- ApoE 2,3,4 inheritance
- Genes: Apolipoprotein J, TOMM40, Soritilin Related Receptor
- General anesthesia
What help lower the risk for AD due to vascular diseases?
- Prophylactic treatment for HTN
2. Folic acid (lower homocysteine level and risk for AD)
What factor does ApoE4 increase the risk for AD by?
19
What can be done to help reduce risk of AD caused by high serum levels of cholesterol in mid-life?
Statins: May be a good treatment since they reduce the pool of cholesterol in the serum
-May also decrease inflammation and increase secretase levels/lipid turnover
What does apolipoprotein J do (gene identified for increased risk of AD)?
It is a beta-amyloid chaperone protein
What does TOMM40 do (gene identified for increased risk of AD)?
Protein transporter across the mitochondrial membrane
What does soritillin related receptor do (gene identified for increased risk of AD)?
Partitions beta-amyloid away from beta-secretase
What had general anesthesia been shown to cause?
Tau Instability and Beta-amyloid polymerization
What if number of cases of AD worldwide and in the US?
35 million cases worldwide, 5.5 million in the US
By 2050, what is the number of cases of AD expected to be due to an aging population in the US?
13-16 million
What is AD the most common cause of, and what % does this account for on autopsy?
Dementia…accounts for 50-60% on automsy
-When you combine with intracerebral vascular disease, this number goes up by another 13-17%
What % of the AD population is made up by patients with vascular disease?
60-90%
-The vast majority come from those with major infarct
What % of AD patients might be affected by cerebral amyloid angiopathy?
90%
