Molecular Mechanisms of Alzheimers Disease Flashcards
What is dementia?
a syndrome of a chronic or progressive natures in which there is deterioration of function beyond what might be expected from normal aging
What does dementia affect?
learning, memory, thinking, orientation, comprehension, language and judgement
What is vascular dementia?
step wise deficits in the ability due to small strokes in the area that was affected
What are the main types of dementia?
60-75% - Alzheimers
20% - Vascular
What are the pathophysiological features inside the Alzheimers brain?
severe cell loss protein accumulations inflammation oxidative damage spread from hippocampus right through brain into cerebellum and into the spinal cord
What are the genetic links with LOAD?
ApoE
What are the genetic links with EOAD?
APP, PSEN1, PSEN2
What is ApoE?
apolipoprotein is a major component of VLDL found in the brain and liver, that remove excess cholesterol from the blood and carry it to the liver for processing
Where is ApoE secreted?
the glial cells in nascent HDL-like particles
What is the concentration of ApoE in the CSF?
5micrograms/ml
What is the role of ApoE?
to deliver cholesterol and lipid to the neurons and in reverse cholesterol transport to the blood
as a ligand in receptor mediated endocytosis of lipoprotein particles in the CNS
What are the receptors for ApoE?
LDLR and LRP1
Which ApoE receptor has a faster endocytosis rate?
LRP1
What are the three different forms of ApoE and what are their different amino acids?
ApoE2 - cys 112, cys 158 - 8%
ApoE3 - cys 112, arg 158 - 77%
ApoE4 - arg 112, arg 158 - 15%
What are the risk factors associated with ApoE4?
atherosclerosis, CAA, tauopathies, DLB, PD, MS, AD
What is the ApoE4 genotype assciated with?
more extensive plaques and tangles high CSF concentrations of soluble Ab impaired synaptic plasticity increased hippocampal atrophy more brain inflammation
What is the role of ApoE in amyloid removal?
ApoE containing particules sequester Ab and modulate the cellular uptake of an ApoE-Ab complex by receptor mediated endocytosis
glial = protective, neuronal = toxic
How does ApoE4 slow down the removal of Ab?
switches clearance from LRP1 to VLDLR slowing internalisation and removal
How does ApoE facilitate removal of Ab?
facilitates the binding and internalisation or clearance by enzymes such as neprilysin
What enzyme helps clear Ab?
neprilysin
What are potential methods of targetting ApoE4?
Conversion of E4 to E3 by small MW structure correction
Increase lipidation of E4
Ab decoy proteins interfering wiht ApoE4 and Ab interaction
ApoE4 antibodies
ApoE mimetic peptides reversing effects of ApoE4
Gene transfer of ApoE2 in place of E4
What are the risk genes in LOAD?
TREM2 - increases 3-fold, also associated with PD
PLD 3 - over-expression leads to reduction in Ab levels
What are the risk mutations in EOAD?
APP
PSEN1
PSEN2
What is the effect of APP?
increases Ab 2-3x by altering the cleavage efficiency of b-secretase - Swedish Mutation
What is the effect of PSEN1 and PSEN2?
components of y-secretase which cleaves APP into Ab fragments
PSEN 1- chromosome 14 and PSEN 2 on chromosome 1
How does APP alter the amount of Ab produced?
a-secretase cleaves leaving Ab 1-40 which is neuroprotective
BACE-1 cleaves at a higher point leaving Ab 1-42 which aggregates forming plaques and killing neurons
Swedish mutation alters affinity for BACE 1 resulting in more Ab 1-42
What is the cholinergic hypothesis?
loss of the cholinergic projections from NBM to cortex and hippocampus
How is neuronal degeneration supported by the cholinergic hypothesis?
loss of Choline Acetyltranferase (ChAT)
reduction in presynaptic choline transporter
reduction in NBM cholinergic neurons
What is the therapeutic intervention methods for the cholinergic hypothesis?
muscarinic receptor antagonists, AChEIs
What are the current therapies associated with the cholinergic hypothesis?
Tacarine
Donepizil
Rivastigmine
Galantamine
What is the problem with the current therapies associated with the cholinergic hypothesis?
effects are temporary
only 40% of patients respond to treatment
What is the theory behind the glutamate/calcium dysregulation hypothesis?
Ab oligomers enhance glutamate release and block uptake by astrocytes through EAAT - glutamate transporters
Glutamate in cleft increases activating NMDA receptors and increasing Ca influx which activates pathways for neuronal shrinkage and synaptic loss
What is the result of the glutamate/calcium dysregulation
Tau phosphorylation and neuronal death
What survival pathway is inhibited by glutamate?
CAMK II, ERK, pCREB
What is the current treatment affecting the glutamate hypothesis?
Memantine - voltage dependent, non-competitive NMDA receptor antagonist
used for moderate AD or those who cannot take AChEIs
What is the Amyloid Hypothesis?
Ab - generation causing oxidation, excitotoxicity, aggregation, inflammation and tau
What are the potential therapeutic strategies involving the preventing of Ab 1-42 production?
preventing Ab 1-42 production by potentiating a-secretase, or inhibiting b/y secretases
What are the potential therapeutic strategies involving the prevention of aggregation?
Ab-oligomerisation inhibitors
selective amyloid lowering agents
tau aggregation inhibitors
What are the potential therapeutic strategies involving promoting removal of Ab?
vaccines - however have had to stop due to strokes and death as a result of blood vessel ruptures
What are the current drugs being trialled for amyloid processing?
a-secretase induce
y-secretase inhibitor
BACE - inhibitors
What is the Tau hypothesis?
the highly soluble, microtubule binding protein is hyperphosphorylated, destabilising microtubules causing impairments in axonal transport and neuronal dysfunction
What is the current treatment for the Tau hypothesis?
Using Methylene blue prevents aggregation - in P3 trial
How does the brain normally neutralise free radicals?
Glutathione system
Superoxide dismutase
Catalase
What can oxidative stress be caused by?
aging, food contaminents, environmental pollutio, cigarettes, amyloid, inflammation and injury
What are the problems with antioxidant treatment?
VitC does not cross blood brain barrier
Vit E is tightly regulated in the brain
Only 3/24 clinical trials have yielded successful results
What is interesting about people with arthritis?
Less likely to get AD
NSAIDs - didn’t prevent onset
Statins aren’t tested yet
What are the new targets in the treatment of AD?
Humanin
a7nAChRs
What is significant about a7AChRs?
Ab induces the expression
What happens upon activation of a7nAChRs?
facilitates neurotransmission and synaptic plasticity
induces LTP
supports learning and memory
improves attention and memory
What are the interactions of a7nAChRs with Ab?
found in amyloid plaques
has extremely high affinity for Ab
can mediate the internalisation of Ab and inflammatory response
blocks amyloid toxicity
What are the potential therapeutics targeting nAChRs?
agonists - rapid desensitisation but cognitive enhancing and anti-inflammatory
antagonists - block adverse effects of Ab on accumulation and toxicity, not enhancing and block synaptic plasticity
How are mice modelled in AD?
Use of AD mice with swedish mutation
Use of Odor Span Task
What are the features of the Tg2576 mouse model?
APP gene 10months show learning difficulties 1 year - some plaques 15-18months - like human brain Struggled with Odor Span Task from 4 months Nicotine improved learning
What is humanin?
24aa peptide only found in AD brain which protects against toxicity and is neuroprotective in stroke models
What is significant about humanin expression?
co-expresses with amyloid as an early biomarker for AD
Where is Humanin produced?
made by mitochondria to be exported to neighbouring cells and protects against amyloid toxicity
