Molecular Mechanisms in Alzheimer's Disease Flashcards
Describe the molecular mechanisms which cause Alzheimer's-type pathology Discuss the potential risk factors for the development of AD Identify the current therapeutic approaches being researched to treat AD and their molecular targets Criticallt evaluate the various types of in vivo and in vitro experimental approached being utilised in AD research
What is cerebral amyloid angiopathy?
The deposition of amyloid-beta around blood vessels
How many potential phosphorylation sites are there on tau, and where are they located?
85, mostly around serine and threonine residues
How many moles of phosphate does tau contain in the normal adult brain?
2-3 moles of phosphate per mole of protein
How many moles of phosphate does tau contain in the AD brain?
Up to 8-10 moles of phosphate per mole of protein
Name 2 tau protein kinases involved in tau phosphorylation
Glycogen synthase kinase 3 beta (GSK3-beta) and cyclin-dependent kinase 5 (Cdk5)
Name the precursor protein of beta-amyloid
Amyloid precursor protein (APP)
What does non-amyloidogenic cleavage of APP produce?
APP soluble-alpha, thought to be neurotrophic
Which enzymes cleave APP?
APP alpha secretase and APP beta secretase
Where does APP gamma secretase cleavage take place?
Mostly in endosomes, but it can take place on the cell membrane
Where does APP alpha or beta secretase cleavage take place?
Cell membrane
Name a candidate enzyme for APP beta secretase
BACE-1
What is BACE-1?
A transmembrane protein which cleaves neuregulin, a protein involved in the formation of myelijn
Name a candidate enzyme family for APP alpha secretase
The ADAMS family, consisting of disintegrins and metalloproteinases which cleave TNF-alpha
Why is APP gamma-secretase not a good therapeutic target?
It is very important in mediating intramembrane proteolysis and clearing other proteins, so targeting it would have a wide range of side effects
Name the main amyloid-beta efflux (clearance) protein at the blood-brain barrier
Low-density lipoprotein receptor-related protein 1 (LRP1)
What functions are many AD risk genes involved in?
Lipid metabolism, inflammation, and synaptic functioning
State 5 environmental risk factors for AD
Ageing, type II diabetes, hypertension, TBI, smoking, and female gender
How do must current therapies improve the symptoms of AD?
They increase the bioavailable aceylcholine in the brain
Name two disease-modifying stategies that have been trialled for AD, and state why they are not currently available
Gamma-secretase inhibitors - too many side effects
BACE inhbitors - side effects on the retina and skin; some are hepatotoxic
Why did amyloid-beta ‘vaccination’ trials have to be stopped in humans?
Patients started dying of septic encephalopathy. (Post-mortem examination showed that the vaccine had successfully removed beta-amyloid)
Why might current trials of disease-modifying treatments be failing?
They are being trialled too late in the disease stage - they might be more effective in mild cognitive impairment patients, or even earlier if there was a way of identifying patients
Name 2 amyloid antibodies currently in phase III trials
Aducanumab, targeting plaques and oligomers
Crenezumab, targeting oligomers
What is methylene blue, and why are trials of it controversial?
A tau aggregation inhibitor. Trials are controversial are side effects include developing blue eyes and urine, so the placebo effect may be contributing to its effects as patients know they are on it
Why have anti-diabetic drugs been proposed as treatments for AD?
Some studies have found that they may decrease the risk of dementia - e.g. Hsu et al in 2011 published a cohort study showing that metformin decreased the risk of dementia, and Craft et al in 2012 published a RCT which found that intranasal insulin improved cognition. Howeber, a case-control study by Imfeld et al in 2012 found that metformin increased dementia risk, so the evidence is mixed
State 2 advantages of in vitro models of AD
Simpler to work with, allow the effects on 1 cell type to be isolated
State 2 advantages of in vivo models of AD
The effects on memory can be seen, amyloid plaques form in vivo but not usually in vitro
Why are mice typically used to study AD?
They are short-lived, metabolically similar to humans, and can be modified transgenically
Describe the histopathological changes in mouse models of AD
Plaques, neurofibrillary tangles, synapse loss, glial pathology, and astrocytosis - but no massive neuronal loss
Describe two methods of developing rodent models
Transgenics and homologous directed recombination
Give two limitations of transgenic rodent models of AD
Uptake and expression of the transgene varies, and limited neuronal loss is exhibited
Give 2 limitations of homologous directed recombination rodent models of AD
It takes many mutations to develop pathology analogous to AD, and tau is too large a protein to easily make a knock-in of
Describe the pathology developed after intracerebral injection of amyloid pathology vectors in mice
Hyperphosphorylated tau but no neurofibrillary tangles
What is the most common rodent model of AD?
APP transgenics
Which disease are most tau transgenic rodents used to study?
Frontotemporal dementia
Name three tests used to test spatial memory in rodents
Morris water maze, Y waze, radial maze
Which type of memory is tested by an object recognition test?
Working memory
Give 3 advantages of rat models over mouse models
Rats have bigger brains, exhibit more complex behaviour, and have tau isoforms more similar to humans
