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

1
Q

What is cerebral amyloid angiopathy?

A

The deposition of amyloid-beta around blood vessels

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2
Q

How many potential phosphorylation sites are there on tau, and where are they located?

A

85, mostly around serine and threonine residues

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3
Q

How many moles of phosphate does tau contain in the normal adult brain?

A

2-3 moles of phosphate per mole of protein

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4
Q

How many moles of phosphate does tau contain in the AD brain?

A

Up to 8-10 moles of phosphate per mole of protein

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5
Q

Name 2 tau protein kinases involved in tau phosphorylation

A

Glycogen synthase kinase 3 beta (GSK3-beta) and cyclin-dependent kinase 5 (Cdk5)

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6
Q

Name the precursor protein of beta-amyloid

A

Amyloid precursor protein (APP)

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7
Q

What does non-amyloidogenic cleavage of APP produce?

A

APP soluble-alpha, thought to be neurotrophic

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8
Q

Which enzymes cleave APP?

A

APP alpha secretase and APP beta secretase

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9
Q

Where does APP gamma secretase cleavage take place?

A

Mostly in endosomes, but it can take place on the cell membrane

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10
Q

Where does APP alpha or beta secretase cleavage take place?

A

Cell membrane

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11
Q

Name a candidate enzyme for APP beta secretase

A

BACE-1

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12
Q

What is BACE-1?

A

A transmembrane protein which cleaves neuregulin, a protein involved in the formation of myelijn

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13
Q

Name a candidate enzyme family for APP alpha secretase

A

The ADAMS family, consisting of disintegrins and metalloproteinases which cleave TNF-alpha

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14
Q

Why is APP gamma-secretase not a good therapeutic target?

A

It is very important in mediating intramembrane proteolysis and clearing other proteins, so targeting it would have a wide range of side effects

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15
Q

Name the main amyloid-beta efflux (clearance) protein at the blood-brain barrier

A

Low-density lipoprotein receptor-related protein 1 (LRP1)

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16
Q

What functions are many AD risk genes involved in?

A

Lipid metabolism, inflammation, and synaptic functioning

17
Q

State 5 environmental risk factors for AD

A

Ageing, type II diabetes, hypertension, TBI, smoking, and female gender

18
Q

How do must current therapies improve the symptoms of AD?

A

They increase the bioavailable aceylcholine in the brain

19
Q

Name two disease-modifying stategies that have been trialled for AD, and state why they are not currently available

A

Gamma-secretase inhibitors - too many side effects

BACE inhbitors - side effects on the retina and skin; some are hepatotoxic

20
Q

Why did amyloid-beta ‘vaccination’ trials have to be stopped in humans?

A

Patients started dying of septic encephalopathy. (Post-mortem examination showed that the vaccine had successfully removed beta-amyloid)

21
Q

Why might current trials of disease-modifying treatments be failing?

A

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

22
Q

Name 2 amyloid antibodies currently in phase III trials

A

Aducanumab, targeting plaques and oligomers

Crenezumab, targeting oligomers

23
Q

What is methylene blue, and why are trials of it controversial?

A

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

24
Q

Why have anti-diabetic drugs been proposed as treatments for AD?

A

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

25
Q

State 2 advantages of in vitro models of AD

A

Simpler to work with, allow the effects on 1 cell type to be isolated

26
Q

State 2 advantages of in vivo models of AD

A

The effects on memory can be seen, amyloid plaques form in vivo but not usually in vitro

27
Q

Why are mice typically used to study AD?

A

They are short-lived, metabolically similar to humans, and can be modified transgenically

28
Q

Describe the histopathological changes in mouse models of AD

A

Plaques, neurofibrillary tangles, synapse loss, glial pathology, and astrocytosis - but no massive neuronal loss

29
Q

Describe two methods of developing rodent models

A

Transgenics and homologous directed recombination

30
Q

Give two limitations of transgenic rodent models of AD

A

Uptake and expression of the transgene varies, and limited neuronal loss is exhibited

31
Q

Give 2 limitations of homologous directed recombination rodent models of AD

A

It takes many mutations to develop pathology analogous to AD, and tau is too large a protein to easily make a knock-in of

32
Q

Describe the pathology developed after intracerebral injection of amyloid pathology vectors in mice

A

Hyperphosphorylated tau but no neurofibrillary tangles

33
Q

What is the most common rodent model of AD?

A

APP transgenics

34
Q

Which disease are most tau transgenic rodents used to study?

A

Frontotemporal dementia

35
Q

Name three tests used to test spatial memory in rodents

A

Morris water maze, Y waze, radial maze

36
Q

Which type of memory is tested by an object recognition test?

A

Working memory

37
Q

Give 3 advantages of rat models over mouse models

A

Rats have bigger brains, exhibit more complex behaviour, and have tau isoforms more similar to humans