Alzheimer's Disease

Question 1

What is Alzheimer’s Disease?

Answer 1

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

Question 2

What are the intracellular features of AD?

Answer 2

• Accumulation of amyloid beta and hyperphosphorylated tau
• Mitochondrial dysfunction (becoming clumped and round)
• Oxidative stress and damage

Question 3

What is tau? Where is it usually phosphorylated?

Answer 3

• Microtubules associated protein which facilitates microtubule assembly
• For axogenesis phosphorylation at Ser199/202 and Thr205 by PKA and MARK

Question 4

How is tau pathologically phosphorylated?

Answer 4

• Phosphorylation of Ser262 and Thr231 in pre-tangles and Ser422 in neurofibrillary tangles
• Mediated by GSK-3beta

Question 5

How is amyloid cleaved in the non-amyloidgenic pathway?

Answer 5

• APP (amyloid precurosor protein) cleaved by gamma secretase to make P3 (unknown function) and APP-alpha which is potentially neuroprotective and soluble

Question 6

How is amyloid cleaved in the amyloidgenic pathway?

Answer 6

APP is cleaved by beta secretase to form sAPP-beta (which is smaller) nd amyloid beta which forms sticky fragments producting plaque

Question 7

What is early onset AD (EOAD)?

Answer 7

• 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

Question 8

What mutations are associated with EOAD?

Answer 8

• 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

Question 9

What is EOAD with complex inheritance?

Answer 9

• 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

Question 10

What is late onset AD (LOAD)?

Answer 10

• 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

Question 11

What genes have been associated with AD?

Answer 11

• 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

Question 12

What is APOE?

Answer 12

• 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

Question 13

How is APOE linked to AD?

Answer 13

APOE e4 increases risk of AD and is associated with earlier onset, with hommozygotes incurring a 3/5x risk and heterozygotes a 2x risk

Question 14

What are the other forms of APOE and what effect do they have on AD risk?

Answer 14

• 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

Question 15

What is the function of APOE in the brain?

Answer 15

• Prodominantely produced by astrocytes, microglia and sometimes neurons (in certain conditions)
• Facilitates lipid transport to neurons, synaptogenesis, cerebrovascular integrity, hippocampal neurogenesis and neuroimmune modulation

Question 16

How do different APOE forms affect it’s efficacy in clearing amyloid?

Answer 16

• 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

Question 17

What support is there for the idea that APOE E4 is a gain of function mutation?

Answer 17

• 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

Question 18

What support is there for the idea that APE is a toxic gain of cuntion allele?

Answer 18

• 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

Question 19

What are the diergent features of different forms of AD?

Answer 19

• 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