Alzheimer's Disease Flashcards
Alzheimers is the most common form of ….
dementia
when do most patients develop clinical signs
in their 70’s
causes abnormalities in
memory
problem solving
judgement
behaviour
What is the problem with diagnosing Alzheimer’s
accuracy
autopsy is the only definitive diagnostic tool currently
The incidence of Alzheimer’s increases with
age
Other than age what are some other risk factors of Alzheimer’s
family history (hereditary)
women more susceptible
- pre-disposing factors on X chromosome
high BP
smoking
obesity
low physical/mental activity
severe head trauma
What does Alzheimer’s disease change in brain structure
cerebral cortex shrivels
- damaging reas involved in memory, thinking and planning
shrinkage of the hippocampus
- struggles to form new memories
ventricles grow larger
narrow gyri/ wide sulci
The pathology of Alzheimer’s demonstrate 2 lesions. What are these two lesions?
senile plaques of beta amyloid = extracellular
neurofibrillary tangles of phosphorylated tau = intracellular
- found in dead/dying neurons
briefly how are tau tangles formed
phosphorylated microtubules (tau is a microtubule associated protein)
tau become hyperphosphorylated and aggregates leading to tangles
How do the tangles and plaques spread around the brain?
in a predictable pattern
- rate depends on age of diagnosis and other health conditions
What is the average prognosis for Alzheimer’s patients
8 years but some live up to 20
What particular findings classify the earliest stage of Alzheimer’s disease
plaques and tangles form in brain in areas affecting memory, learning, thinking and planning (in a contained area)
may appear 20 years before diagnosis
What particular findings classify the mild to moderate stage of Alzheimer’s disease
begins to spread
- more plaques and tangles form in brain areas affecting memory, learning, thinking and planning
- begins to affect speech and spatial awareness
- may experience confusion and difficulty expressing thoughts and feelings
- problems affect work and social life
- this stage lasts 2 to 10 years
What particular findings classify the advanced stage of Alzheimer’s disease
spreading continues
- cortex severely damaged by widespread neuronal death and brain shrinks
- patient dependant on caregivers
- loss of speech, apathy and exhaustion
- cause of death usually by secondary infection
- stage lasts 1 to 5 years
Alzheimer’s is difficult to diagnose in early stages with mild symptoms. What techniques can be used for diagnosis?
patient history
neuroimaging (CT, MRI)
- to detect abnormalities in medial temporal lobe (where AD progression usually beings)
neuroimaging (PET)
- to detect decreased blood flow in parietal and temporal lobes
alterations of serum proteins
What are some new methods for detecting Alzheimer’s
mass spectrometry of blood samples for Beta amyloid
1-5% of Alzheimer’s cases have a genetic change identified. These result in an earlier age of onset, what is that age?
65
What are the 3 main loci linked to familial AD
amyloid precursor protein (APP)
presenilin 1 (PSEN1)
presenilin (PSEN2)
mutations in any can lead to Alzheimer’s
What loci, when a mutation is present, can increase the risk of having Alzheimer’s disease
apolipoprotein E (APOE)
- APOE4 allele is link to a 3x risk in heterozygotes and a 15x risk in homozygotes
What is the amyloid precursor protein (APP)?
transmembrane protein
- large extracellular domain
- small intracellular domain
gene has 19 exons (3,8 and 15 can be alternatively spliced)
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
Beta amyloid causes amyloid plaques found in AD. What is the length of beta amyloid?
40 amino acids
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)
long beta amyloid causes 10-50% of all early onset AD. They cause what in the brain
extracellular beta amyloid fibrils and senile plaques
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
may act as a growth factor
- generation, differentiation and migration of neurons
- axon or dendrite outgrowth
- regulation of synaptic function as it can be found at the neuronal synapse
Binds to molecules in the extracellular matrix like:
- heparin
- laminin
May be involved in cell-matrix adhesion and vesicle trafficking
When APP is cleaves is produces beta amyloid and amyloid precursor protein intracellular domain (ACID). What is the function of ACID?
may translocate to the nucleus and act as a transcription factor (not 100% sure)
ACID may also bind to G proteins
- ?involved in cellular signalling
Presenilin-1 is a subunit of gamma secretase complex which cleaves amyloid precursor protein (APP). What is this protein?
multi-pass transmembrane protein found in brain cells
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
Presenilin-2 is another subunit of the gamma secretase complex which cleaves APP. What is this protein?
multi-pass transmembrane protein found in brain cells
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) producing:
- a different soluble fragment
- a different membrane bound fragment
the membrane bound fragment is cleaved by gamma secretase to produce:
-beta amyloid
- ACID
When APP is cleaved by beta secretase why does beta amyloid get produced?
beta secretase cleaves at a different site on APP
alpha secretase cleaves APP at a site which cute the beta amyloid portion in half
What is the evidence for beta amyloid being the cause of Alzheimer’s disease?
- AB toxic to neurons in culture as accumulation in cytosol indices apoptosis
- AB controls cleavage/phosphorylation of tau leading to neurofibrillary tangle generation
- another identifier for AD - APP gene mutation adjacent to beta secretase cleavage site reducing the ability to fo beta secretase to cleave APP therefore no AB formed
What is the evidence that beta amyloid is not the causative agent of Alzheimer’s disease?
therapeutic monoclonal antibodies against AB have failed
What did research using mice with APP, APLP-1 or APLP-2 deletions show?
APP and APLP-2 may play a role in regulating structure, function and signalling of neuromuscular synapses
Apolipoprotein E (APOE) is a protein synthesised mainly in the liver but also found in the brain, cerebrospinal fluid, blood, kidneys and spleen. What is the function of Apolipoprotein E (APOE) in plasma?
transports:
- lipoproteins
- phospholipids
- fat-soluble vitamins
- cholesterol
main component of lipoproteins in plasma
What are the primary producers of APOE in nervous system?
non-neuronal cell types like astroglia and microglia
what is the role of Apolipoprotein E (APOE) in neurons?
neurons express receptors for APOE as it transports cholesterol to neurons
Apolipoproteins (APO) are lipid free proteins but APOE can bind to a specific receptor. What receptor is this?
LDL receptors and is a ligand for receptor-mediated endocytosis.
APOE locus has 3 alleles. What are these alleles and which is a common genetic risk factor for AD?
APOEe2, APOEe3, APOEe4
APOEe4 is a risk factor for AD
- decreased range of onset
- increased senile plaque density
- impaired cognitive function
APO help break down what protein? How does APOEe4 change this?
help breakdown beta amyloid
APOEe4 is not as effective leading to excess amyloid beta build up in the brain
Research shows that APOEe4 allele copy number has an inverse relationship with brain choline acetyltransferase activity. How is this related to AD?
choline acetyltransferase deficiency found in AD
- leading to a defect in processing acetylcholine neurotransmitter
Tau is a microtubule binding protein. What is its function in the nervous system?
stabilise and regulate orientation of microtubules in neurons, astrocytes and oligodendrocytes
- modulates the stability of axonal microtubules
What gene is Tau encoded by?
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 phosphorylated by protein kinases
- mutated tau is 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 hyper-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
There are two hypothesis for how amyloid beta leads to AD. What are these two hypotheses?
amyloid cascade hypothesis
modified amyloid cascade hypothesis with the role of tau
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 AB
research with transgenic mice with knockout of zinc transporter 3 revealed what?
decreased brain zinc and decreased amyloid
What are some other features of zinc that could relate to AD?
zinc metalloproteases which degrade AB
affects calcium signalling (excitotoxicity)
How can zinc be beneficial in AD?
rease in zinc leads to less copper binding to AB and being endocytosed
- copper leads to oxidative stress in neurons
