Alzheimers Flashcards
What is the biggest risk factor for alzheimers disease?
Age
What are other risk factors apart from age for AD?
- Family history
- Heredity
-Women more susceptible to Alzheimer’s
disease- Predisposing factors on X‐chromosome
- Estrogen protects against mitochondrial
toxicity in young women
- High blood pressure
- Smoking
- Obesity
- Low physical activity
- Low mental activity
- Severe head trauma
- unconsciousness and retrograde amnesia
What are the physical features in a brain affected by AD?
- Neuronal death and tissue loss
throughout the brain - Cortex shrivels, damaging
areas involved in memory,
thinking and planning - Shrinkage of hippocampus:
key role in forming new
memories - Ventricles (fluid-filled spaces)
grow larger - Nearly all brain functions
affected
What are the two lesions of alzheimers disease?
- Senile plaques of β‐amyloid (Aβ) (extracellular)
- Neurofibrillary tangles of phosphorylated tau,
a microtubule- associated protein (intracellular); found in dead and dying neurons
What are the earliest stages of Alzheimer’s in the brain?
- Plaques and tangles form in brain
areas affecting memory, learning,
thinking and planning - May appear 20 years before
diagnosis
What are the mild to moderate stages of alzheimers in the brain?
- More plaques and tangles form in
brain areas affecting memory,
learning, thinking and planning - Affects speaking and understanding
speech, spatial awareness - May experience confusion and
difficulty expressing thoughts and
feelings - Problems serious enough to affect
work or social life - Stage lasts 2 to 10 years
What are the advanced stages of alzheimers in the brain?
- Cortex severely damaged,
widespread neuronal death, brain
shrinks - Stage lasts 1 to 5 years
- Completely dependent on
caregivers - Loss of speech, apathy and
exhaustion - Cause of death usually external
(e.g. infection of pressure ulcers or
pneumonia)
What are the techniques used to diagnose alzheimers disease?
What are 3 main loci linked to familial AD? (mutations in these)
Amyloid precursor protein (APP)
Presenilin 1 (PSEN1)
Presenilin 2 (PSEN2)
Mutations in these can cause Alzhiemers
What are the genetic risk factors in AD?
- Apolipoprotein E (APOE)
-APOEε4 allele 3x risk in heterozygotes
and 15x in homozygotes
What is the amyloid precursor protein (APP)?
- Transmembrane protein
- Large extracellular domain and small intracellulr domain
- Gene has 19 exons
APP can be alternatively spliced into 3 variants : APP695, APP751 and APP770. Which of these is most abundant in the brain?
APP695
APP can be cleaved into different peptides by alpa, beta and gamma secretases. What are one of these peptides known as?
beta amyloid
amyloid precursor protein (APP) mutations can alter how the protein is cleaved. There is over 25 mutations found that can lead to incorrect beta amyloid. These mutations cause a change in beta amyloid length to
42 or 43 amino acids in length
- making it more hydrophobic and amyloidogenic (more likely to aggregate)
There are other proteins in the family of Amyloid precursor protein (APP). These are APLP1 and APLP2, why are these not involved in AD?
these proteins are not amyloidogenic (cannot form aggregates)
What is the function of APP?
Primary function of APP is not clear
May act as a growth factor:
- generation, differentiation and migration of neurons (within brain)
- Neurite (axon or a dendrite) outgrowth
- Regulation of synpatic function
Binds to molecules in the extracellular matrix like:
- heparin
- laminin
May be involved in cell-matrix adhesion and vesicle trafficking
What is presenilin-1?
Multi-pass transmembrane protein found in brain cells
Subunit of gamma-secretase complex: cleaves amyloid precursor protein (APP)
Presenilin-1 has 40 different possible mutations which leads to altered cleaves to APP. What is the pattern of inheritance involved when this protein is mutated? How does this alter the onset of AD?
Autosomal dominant
onset lowers to 28 years old
When normal Presenilin-1 cleaves normal amyloid precursor protein (APP) what does this result in?
P3 and ACID
What is presenilin-2?
Multi-pass transmembrane protein in brain cells
Subunit of gamma-secretase complex: cleaves amyloid precursor protein (APP)
mutations in Presenilin-2 are rare as only 6 mutations have been identified. If this gene runs in the family what is the inheritance and the consequence to AD onset?
recessive autosomal inheritance
early onset
In normal conditions, when APP is cleaved what is produced?
APP cleaved by alpha secretase first produces:
- a large soluble fragment
- small membrane bound fragment
-the smaller fragment is then further cleaved by gamma secretase producing:
- release P3 peptide and ACID
In pathogenic conditions, How is APP cleaved and what does it produce?
APP cleaved by beta secretase (BACE1) to produce a different soluble fragment
Remaining membrane bound fragment is cleaved by y-secretase to form beta-amyloid
Beta-amyloid can form b-amyloid fibrils and senile plaques
What is beta amyloid?
- Acutely toxic to neurons in culture
- Accumulation in cytosol induces apoptosis
- Controls cleavage and phosphorylation of tau, both of which are crucial for neurofibrillary tangle generation
What is the function of Apolipoprotein E
Transports lipoproteins, phospholipids, fat‐solube vitamins, and cholesterol in the lymphatic system and blood
Mainly synthesised in the liver
what is the role of Apolipoprotein E (APOE) in neurons?
Neurons express receptors for APOE and the APOE transports cholesterol to neurons
Apolipoproteins (APO) are lipid free proteins but APOE can bind to a specific receptor. What receptor is this?
Apolipoprotein E (ApoE) binds to LDL recepto and is a ligand for receptor‐mediated
endocytosis
ApoE locus has three alleles. What are they and which one is the most common for a genetic risk factor for AD?
E2, E3, E4
E4 is a risk factor for AD
- Associated with decreased age of onset, increase senile plaques and impacts cognitive function
APO help break down what protein? How does APOEe4 change this?
Apoplipoproteins help to break down beta amyloid
APOEε4 not as effective, leads to excess amyloid build up in the brain
What is the function of Tau?
Microtubule binding protein
- Stabilize and regulate orientation of microtubules in neurons astrocytes and oligodendrocytes
- Modulates the stability of axonal microtubules
What gene is Tau encoded by?
Encoded by the MAPT (microtubule-associated protein tau) gene
What gene is Tau encoded by?
Encoded by the MAPT (microtubule-associated protein tau) gene
mutations in MAPT can cause AD (but not necessary for AD). How is tau proteins altered when there is a MAPT mutation?
tau is usually hyper-phosphorylated by protein kinases
- mutated tau cannot be hyper-phosphorylated and reduces microtubule binding
The lack of microtubule binding to tau leads to what consequences?
destabilised microtubule networks and impaired axonal transport
- as tau cannot bind neurofibrillary tangles form and neuronal death occurs
How do phosphorylated tau proteins cause neurofibrillary tangles?
as tau cannot bind properly to microtubules they form paired helical filaments
- the filaments aggregate causing the tangles
how does native tau become Alz 50?
N terminal region attaches to the to the microtubule binding region (MTBR) induced by further phosphorylation
- inhibits binding to microtubules
How does Alz50 becomes Tau-66?
Alz50 is the most aggregates form then the N-terminal and C-terminal becomes truncated to form Tau-66
What is the importance of tau-66?
Tau-66 has the ability to form neurofibrillary tangles
What is the amyloid cascade hypothesis?
deposition of AB in the brain constitutes the central pathological lesions in AD
What is wrong with the amyloid cascade hypothesis?
amyloid deposition is not strongly correlated with cognitive decline in patients
treatments aimed at beta amyloid have failed
Why is the modified amyloid cascade hypothesis with the role of tau a better explanation of AD?
tau pathway correlates more closely with clinical symptoms of Ad and therefore tau may be more of a key factor in AD
In regards to the channel hypothesis for AD. AB peptides form a channel in the membrane of neurons. What are these channels and what elements do they let through?
large, voltage dependant ion channels
enables Ca2+, Na+, K+ to enter which alters PM potential with ions move when they are not supposed to.
In regards the channel hypothesis for AD. These channels can also insert into the mitochondrial membrane. What does this cause?
disrupts membrane potential
alters Ca2+ handling
induced mitochondrial permeability transition pore (MPTP) opening
- causing the release of cytochrome c inducing apoptosis
How is zinc associated with AD?
zinc has been shown concentrated in amyloid plaques
- zinc also induces aggregation of beta amyloid of AB which has binding sites for zinc
What is the theory behind why zinc is associated with AD?
zinc is released from neuron into synapse
extracellular zinc can then precipitate
