Alzheimer's Disease Flashcards
What is Alzheimer’s Disease?
Characterised by progressive dementia coupled with the extracellular accumulation of amyloid plaques and hyperphosphorylated tau coupled with neuroinflammation
- Causes not only memory loss, but at later stages complete incapacitation
What are the intracellular features of AD?
- Accumulation of amyloid beta and hyperphosphorylated tau
- Mitochondrial dysfunction (becoming clumped and round)
- Oxidative stress and damage
What is tau? Where is it usually phosphorylated?
- Microtubules associated protein which facilitates microtubule assembly
- For axogenesis phosphorylation at Ser199/202 and Thr205 by PKA and MARK
How is tau pathologically phosphorylated?
- Phosphorylation of Ser262 and Thr231 in pre-tangles and Ser422 in neurofibrillary tangles
- Mediated by GSK-3beta
How is amyloid cleaved in the non-amyloidgenic pathway?
- APP (amyloid precurosor protein) cleaved by gamma secretase to make P3 (unknown function) and APP-alpha which is potentially neuroprotective and soluble
How is amyloid cleaved in the amyloidgenic pathway?
APP is cleaved by beta secretase to form sAPP-beta (which is smaller) nd amyloid beta which forms sticky fragments producting plaque
What is early onset AD (EOAD)?
- Dominantly inherited mutations, accounts for ~1% of AD patients
- Onset at ages 30-60 years which varies with severity of mutation
- Unique involvement of the basal ganglia which is not seen in other types
What mutations are associated with EOAD?
- Mutations of APP leading to enhanced cleavage by beta-secretase
- Mutations of PSEN 1/2 which increase gamma secretase activity, potentially to the point of ober activity and so there is more beta-secretase cleavage
What is EOAD with complex inheritance?
- Not autosomal dominant inheritance but a genetic link which is characterised by a more extreme phenotype likely affected by environmental factors
- Onset <65 years, ~4% of AD patients
- Not sure however what mutations or environmental factors are involved
What is late onset AD (LOAD)?
- Disease onset >65 years accounting for 95% of AD patients
- Some familial cases but mostly sporadic
- Causes are multiple and complex with various environmental factors and gene loci identified
What genes have been associated with AD?
- APOE4 mutations induce moderate risk and APOE4 heteroxygotes and ABCA also induce a somwhat lower risk, all have similar functions and are associated with cholesterol metabolism
- Most genes are associated with amyloid pathology with only one gene linked to tau pathology
- QUite a few genes are also linked to the immune response
- Other genes linked are associated with endocytosis and the cytoskeleton
What is APOE?
- Encodes apolipoproteins, proteins which bind to lipids to form lipoproteins
- These are primary modulators of cholesterol in the brain and play a complex role in lipid and protein homeostasis
How is APOE linked to AD?
APOE e4 increases risk of AD and is associated with earlier onset, with hommozygotes incurring a 3/5x risk and heterozygotes a 2x risk
What are the other forms of APOE and what effect do they have on AD risk?
- APOE e2 is rara and may be protective, if AD occurs in someone with this gene it usually develops later in life
- APOE e3 is the most common and is completely neutral
What is the function of APOE in the brain?
- Prodominantely produced by astrocytes, microglia and sometimes neurons (in certain conditions)
- Facilitates lipid transport to neurons, synaptogenesis, cerebrovascular integrity, hippocampal neurogenesis and neuroimmune modulation
How do different APOE forms affect it’s efficacy in clearing amyloid?
- If amyloid is bound to E2 or E3 it can easily be cleared from the brain (both better than E4) and disposed or broken down (E2>E3>E4)
- E3 is better at binding amyloid beta to pull it out of production (E3>E4)
- Even after the execution of the amyloidgenic pathway plaque deposition is still more likely with E4
What support is there for the idea that APOE E4 is a gain of function mutation?
- APOE must be lipidated to function and in astrocytic APOE E4 lipid carrying is depleted
- Lipidation of APOE is carried out by abca1(and abca7 is an AD risk factor)
- Overexpression of abca1 increases lipidation of APOE and anhances amyloid clearance
What support is there for the idea that APE is a toxic gain of cuntion allele?
- Cerebral ischemia (blocked blood supply a common risk of AD) has been shown to lead to neuronal overexpression of APOE
- In neurons APOE is cleaved to give toxic fragments
- APOE e4 reduced recycling of glutamate receptors and induced synaptic dysfunction
- APOE e4 expressing astrocytes demonstrate reduced phagocytic capacity and are less able to support neuronal function
What are the diergent features of different forms of AD?
- Pathway to attain pathology differs
- Areas affected slightly differ between EOAD and LOAD
- EOAD can be predicted, opening up a therapeutic window
- LOAD risk can be modified, pre-symptomatic interventions are possible
