Alzheimer’s Flashcards
What are the symptoms of Alzheimer’s?
Confusion
Forgetfulness
Mood swings
Depression and anxiety
Becoming withdrawn
Difficulty with everyday tasks
What are the microscopic features of Alzheimer’s?
Senile plaques - extracellular fribrillar proteins aggregates of beta amyloid
Neurofibrillary tangles - intracellular protein aggregates of hyperphosphorylated tau protein
What sort of things increase your risks of Alzheimer’s?
Depression
Traumatic head injury
Cardiovascular factors
Cerebrovascular factors
Aging
NSAID use and Alzheimer’s
Chronic use of NSAIDs for conditions such as rheumatoid arthritis is associated with lower incidence of AD
Ibuprofen has been shown to slow cognitive decline
What are the two categories of AD?
Sporadic Alzheimer’s disease (SAD)
Familial Alzheimer’s disease (FAD)
What causes FAD?
Mutated genes:
APP
PSEN 1
PSEN 2
What is the risk factor associated with SAD?
APoE
What is APP?
The gene that codes for amyloid precursor protein -can yield potentially toxic beta amyloid when it undergoes proteolytic processing with the membrane of CNS neurons
What is PSEN-1?
Presenilin-1
The gene that codes for the protein that functions as the catalytic subunit of gamma secretase - an intramembrane proteolytic anzyme complex that cleaves specific proteins with the plane of the plasma membrane
What is PRSEN-2?
Presenilin-2
Codes for a homologous protein of PSEN-1
What is APoE?
Apolipoprotein-E
A major class of lipid transport proteins with different isoforms having different affinities for LDL and VLDL etc
Is mainly produced in the liver but can be produced by neurons in stressful periods
Produced in the CNS by microglia and astrocytes
What is E4?
An isoform of APoE associated with AD and cardiovascular disease
Paradoxically appears to have a protective role in age related macular degeneration (AMD) - greater source of vision loss in western countries
What is tau?
A microtubule associated protein involved in microtubule stabilisation
What are the three mutation sites of the APP gene?
BACE cleavage site
Gamma secretase cleavage site
Mid domain amyloid beta region
What proteins make up the gamma secretase complex?
PSEN-1 or PSEN-2
Nicastrin
Anterior pharynx defective 1 (APHD1A or APHD1B)
Presenilin enhancer
In total there are four different combinations for the gamma secretase complex
Name a gene mutation in APP that is considered beneficial
A coding mutation (A673T) in the APP gene protects against Alzheimer’s and cognitive decline in the elderly without AD
It results in approximately 40% reduced formation of amyloidogenic peptides in vitro
What is amyloid beta 42?
A 42 amino acid peptide derived from the APP that forms insoluble amyloid fibrils when released from the surface of neurons via intra membrane cleavage by BACE 1
What observations support the amyloid cascade hypothesis?
Amyloid plaques are pathognomonic of AD
Amyloid accumulation in other organs is associated with cellular dysfunction
Amyloid beta 42 is neurotoxic and pro inflammatory (in AD there is a shift toward this form of amylase)
The genetic risk factor (APoE) is associated with an increased amyloid burden
All gene mutations that cause FAD increase amyloid beta 42 compare to the non aggregation version AB 40
What happens in the non amyloidogenic pathway?
APP is first cleaved by alpha secretase
Releasing a soluble ectodomain off APP called s-APP-alpha
And a membrane tethered intracellular C terminal fragment
This is then further cleaved by gamma secretase
Produces a 3-kDa peptide and APP intracellular domain (AICD)
What are the steps of the amyloidogenic pathway?
The products of beta secretase are a soluble ectodomain of APP (sAPP-beta) and a C terminal fragment beta
The 2nd step releases amyloid beta and AICD
What are LDLRs?
Low density lipoprotein receptors
Where do the two amyloid pathways happen?
Non amyloidogenic - the plasma membrane
Amyloidogenic - mainly in endosomes
What happens to AICD?
It is transferred to the nucleus
Where it functions as a transcriptional regulator
What is AICD?
APP intracellular domain
What is pCREB?
The active phosphorylated form of cAMP dependent response element binding protein
What is cAMP dependent response element binding protein
A transcription factor that regulates up to 4000 genes, but in the brain has crucial roles in learning and memory
What is important about AICD interacting with the Galphas subunit of the G protein that drives cAMP-pCREB signalling?
This aids in maintaining spatial memory and inhibiting the amyloidogenic processing of APP.
pCREB is reduced in the prefrontal cortex
What does AICD regulate?
It acts as a transcriptional regulator of the regulatory microRNA (Mir-663) that has multiple roles in the preservation of the stem cell state in neural stem cells
What are some of the beneficial properties of s-APP alpha?
Neuroprotective
Neurotrotrophic
Synaptogenic
LTP enhancing
Memory enhancing
Stimulates adult neurogenesis
What is the pathology behind AD?
Normal physiological conditions equal amounts of APPsa and amyloid beta are produced
During AD ABeta production increases/ clearance decreases and it accumulates in oligomers and plaques inhibit synaptic transmission
What are some methods to increase the amount of APPsa?
Upregulation of alpha secretase expression/ activity
Direct expression and/ or delivery of APPsa or biologically active APPsa sub fragments
What are ways to reduce amyloid beta levels?
Beta gamma secretase inhibitors
Enhanced ABeta degradation or clearance
ABeta directed immuno therapy
How does tau impact on AD?
Tau hyperpolarisation - reduces the binding of tau to microtubules
Sequestration of Hyper tau into neurofibrillary tangles - reduces the amount of tau available to bind to microtubules
What does tau do?
Facilitates microtubule stabilisation within cells and is particularly abundant in neurons
What happens to tau in Alzheimer’s?
It is hyperphosphorylated and then sequestered
What are some therapeutic strategies for targeting hyperphosphorylated tau?
Anti-phosphorylating strategies:
Kinase inhibitors
Aggregation inhibitors enhancing clearance of tau and degradation of aggregates
What are neurofibrillary tangles?
Tau is hyperphosphorylated
Leads to detachment of tau from microtubules
Forms soluble tau aggregates
Then form insoluble paired helical filaments
Form neurofibrillary tangles
What areas of the neuron do mitochondria need to be transported to?
Presynaptic terminal
Axon
Dendritic spine
What determines the long range transport of mitochondria from the soma to the distal axonal and dendritic ends?
The polarity and organisation of neuronal microtubules
How are the charges arranged on neurons?
Axonal microtubules have the + end directed distally and the - is directed towards the soma
What moves mitochondria to the soma?
Cytoplasmic dynein motors
What moves mitochondria in the anterograde direction?
Kinesin motors if the KIF5 family drive mitochondria to the distal axonal regions and synaptic terminals
How is mitochondria moved in the dendritic direction?
Due to the mixed polarity kinesin and dynein motors can transport either in the anterograde or retrograde depending on the microtubule polarity
What do myosin motors do?
They mediate short range movement in presynaptic terminals, growth cones and dendritic spines
What do actin filaments do?
They form the major cytoskeleton architecture
How are mobile mitochondria recruited?
Recruited to stationary pools by via dynamic interactions between the docking receptor syntaphilin and microtubules or via actin based anchoring machinery
What is the use of mitochondrial docking mechanisms?
They ensure that stationary mitochondria are adequately distributed within axons and at synapses
What enables the transmission of high velocity nerve impulses?
The high density of Na+ and Na/K ATPases at the nodes of ranvier
Also allows repetitive firing
What is negative synergy?
When the value of the combined entities is less than the value of each entity if it operated alone
Describe the process of negative synergism involving mitochondria, tau and amyloid beta
AB and Tau pathologies are very linked
AB interacts with HP tau and induces neurofibrillary tangles
Fragments of AB and tau are involved in mitochondrial dysfunction with generation of reactive oxygen species
Tau mediated impairment of mitochondrial transport exacerbates energy /nutrient depletion at synapses
What are the three APOE alleles?
APO-E2
APO-E3
APO-E4
Describe APO-E2
It is protective with a 40% reduced risk of AD
Describe APO-E3
It is neutral and regarded as the reference allel
What is APO-E4?
Is a major genetic risk factor that functionally impairs the normal function of APOE in the clearance of extracellular beta amyloid from the brain
What are some stats associated with APO-E4?
15% in general population
40% in AD population
Lowers the age of onset 4-fold relative to APO-E3
Two APO-E4 alleles increase the risk 12-fold
What is APoE?
A 299 amino acid glycoprotein with a molecular mass of 34 kDa
What does APoE do?
Transports cholesterol and other lipids with delivery via cell surface APoE receptors and is a principle ligand for the LDL receptor
Where is APoE produced?
Mainly in the liver
What are the concentrations of APoE in the body?
Plasma - 40-70mg/ml
CSF - 3-5mg/ml
What are the three isoforms of APOE?
APO-E2
APO-E3
APO-E4
Where is APOE produced in the brain?
By astrocytes
Can also be expressed by microglia and neurons under pathological conditions
What promotes the formation of extracellular amyloid?
When APoE is codepositied with beta amyloid in senile plaques
Where are APoE binding sites found?
Binding site for it cell surface receptor, cargo lipid and heparin residues are in the extracellular matrix and at the cell surface
What impact does APO-E4 have on APoE and amyloid beta levels?
APO-E4 carriers and AD patients show lower levels of APoE and AB in their CSF than other isoforms suggesting that E4 is less efficient at removing AB from the brain
What causes the break down of the blood brain barrier in AD?
Pericyte loss
How does APO-E4 relate to pericyte levels?
Even one of these alleles shows increased levels of the soluble form of the pericyte marker PDGFR beta in their CSF
What are the current treatments for Alzheimer’s?
Acetyl cholinesterase inhibitors
Low affinity NMDA receptor antagonist memantine
What do acetyl cholinesterase inhibitors do?
They potentials acetylcholine synaptic transmission
These enhance neuronal function but do nothing to delay the underlying pathology
What does the low affinity NMDA receptor antagonist do?
Normalise glutamate activity and reduces glutamate-NMDA excitotoxic cell death in AD and other neurodegenerative diseases
How is the amyloid precursor protein cleaved?
By beta secretase (BACE1) and gamma secretase
To release various isoforms of AB peptide
What is the difference between oligomers and amyloid plaques?
Oligomers have acute synaptotoxic effects
Amyloid plaques lead to inflammatory responses
