Case 1 - Alzheimer's Flashcards
Hallmarks of AD
- Neuronal loss
- Neurofibrillary tangles (tau)
- Senile plaques (Abeta)
- Blood brain barrier disruption
- Lipid disbalance
- Neuroinflammation
timeline of AD hallmarks
- Amyloidbeta
- tau
- brain atrophy
Senile plaques (beta-amyloid) pathogenesis
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
senile plaques pathogenic mechanims
- mitochondrial dysfunction –> ROS
- ion disbalance (Ca)
- cell death cascades activation
tau tangles - pathogenesis
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
tau tangles - pathogenic mechanism
- reduced mitophagy
- mito disfunction –> ROS
- reduced synaptic transmission
BBB disfunction
- 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
lipid disbalance
- 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
neuroinflammation
- 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
brain atrophy
- larger ventricles
- smaller cortex and hippocampus
symptoms
- initially only memory deficit
- later severe cognitive and behavioral symptoms
biomarkers
- low total tau and Ab in CSF since they accumulate in brain
- MRI to measure brain volume
- genetic markers: Apoe4, PS-1/2, APP
genetics
- 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
APP mutation
- 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
PS-1 and PS-2 mutation
- 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
