Case 1 - Alzheimer's

Question 1

Hallmarks of AD

Answer 1

1. Neuronal loss
2. Neurofibrillary tangles (tau)
3. Senile plaques (Abeta)
4. Blood brain barrier disruption
5. Lipid disbalance
6. Neuroinflammation

Question 2

timeline of AD hallmarks

Answer 2

1. Amyloidbeta
2. tau
3. brain atrophy

Question 3

Senile plaques (beta-amyloid) pathogenesis

Answer 3

APP is a transmembrane protein which in AD is cleaved by beta-secretase (on the extracellular domain) and gamma-secretase (intracellular) to create beta-amyloid fragment of 40/52 amino acids long which form extracellular plaques
- normally it is cleaved by alfa not beta
- the Ab fragments are highly hydrophobic so form insoluble
plaques

Question 4

senile plaques pathogenic mechanims

Answer 4

• mitochondrial dysfunction –> ROS
• ion disbalance (Ca)
• cell death cascades activation

Question 4

tau tangles - pathogenesis

Answer 4

In AD tau protein (part of the microtubules in neurons) are hyperphosphorylated and thereby lose their affinity for the microtubules, the tau now accumulates in the neuron leaving the microtubule dysfunctional and making transport to and from the soma very difficult
- deposition starts in hippocampus - limbic - cortex
- can become extracellular after cell death

Question 5

tau tangles - pathogenic mechanism

Answer 5

• reduced mitophagy
• mito disfunction –> ROS
• reduced synaptic transmission

Question 6

BBB disfunction

Answer 6

• In AD pericytes and tight-junctions are lost which lead to the micro bleeds and brain extraversion of blood-derived substances
• BBB dysfunction leads to cerebral micro bleeds reflecting loss of cerebrovascular integrity
• Mainly in hippocampus
• Loss of efflux transporters –> high levels of blood-derived molecuels

Question 7

lipid disbalance

Answer 7

• Cholesterol –> in the membranes of neurons there are lipid rafts in which many proteins are clustered and stabilised by cholesterol
  This includes; APP and the beta and gamma secretase that cause senile plaque formation
• Sphingolipids –> second messengers that influence many signalling cascades
  • causes more beta-secreatse expression (ceramide)
  • apoptosis

Question 7

neuroinflammation

Answer 7

• During AD there is proliferation of both microglia and astrocytes which induces inflammation
• Misfolded and aggregated proteins (tau tangles and beta-amyloid plaques) bind to pattern recognition receptors (9 of them including 4 TLRs) on microglia and astroglia
• The inflammatory state causes tissue damage, chronic inflammation increasing the severity of the disease

Question 8

brain atrophy

Answer 8

• larger ventricles
• smaller cortex and hippocampus

Question 9

symptoms

Answer 9

• initially only memory deficit
• later severe cognitive and behavioral symptoms

Question 10

biomarkers

Answer 10

• low total tau and Ab in CSF since they accumulate in brain
• MRI to measure brain volume
• genetic markers: Apoe4, PS-1/2, APP

Question 11

genetics

Answer 11

• Early-onset AD is caused by a number of different single-gene mutations on chromosomes 21, 14, and 1
• PS-2 (1)
• PS-1 (14)
• APP (21)
• APOE4 is the most significant risk gene for late-onset Alzheimer’s disease

Question 12

APP mutation

Answer 12

• The mutations in APP gene promote the formation of toxic Aβ, which will accumulate and form the senile plaques
• The mutations do this by creating a cleavage site in the APP protein for beta-secretase
• Normally only alfa-secretase is able to cleave APP’s extracellular domain which does not produce beta-amyloid

Question 13

PS-1 and PS-2 mutation

Answer 13

• Presenilin proteins influence the γ-secretase– mediated processing of APP, cause a selective increase in the levels of highly Aβ42 species, and accelerate Aβ deposition in the brain

Question 14

APoE4 mutation

Answer 14

• APOE, apolipoprotein E, comes in three variants (alleles) 2, 3, and 4.
• APOE binds to cholesterol and lipids in cells’ environments.
• In AD it is less efficient at clearing the Aβ  this is the APoE4 allele

Question 15

epidimiology

Answer 15

• Alzheimer’s disease is typically a disease of old age. The global prevalence of dementia is reported to be as high as 47 million
• The incidence of Alzheimer’s disease doubles every 5 years, after the age of 65
• Incidence rates of Alzheimer’s disease are slightly higher for women, especially after 85 years of age