Alzheimers Progression Flashcards
What are 3 factors of the AD neuropathological profile?
Amyloid beta plaques
Neurofibrillary tangles & neuropil threads
tau protein
What are 2 cases of AD?
Familial (RARE)
Sporadic
What is AD termed late onset?
After 65 years of age
What are 4 risk factors for sporadic AD?
Ageing
sex (2/3 women)
genetic variants
immunobiography
What 3 genes are mutated in sporadic AD?
Presenilin gene 1 & 2
amyloid precursor protein
Apolipoprotein E
What 2 chromosomes is the presenilin gene located on?
1 and 14
What chromosome is APP gene located on/
21
What chromosome is APOE gene located on?
19
What other neurological disorder can generate early onset AD and why?
Individuals with down syndrome (trisomy 21)
What are 4 other egentic factors?
ATP binding cassette transporter A1
Clusterin gene
Bridging Integrator 1
ECSIT
What does APP produce?
C-terminal fragments under hyrdolysis of secretases by 3 pathways
What is the amyloid cascade hypothesis?
Deposition of amyloid-beta in the brain initiates AD pathogenesis leading to tau deposition, neuron & synaptic loss and cognitive decline
What cleaves APP?
beta secretase
What is the function of tau?
Maintains microtubule structure & cytoplasmic transport function, maintain synaptic structure & function & regulate neuronal signalling
What is the tau hypothesis?
Elevated tau-tau interactions & polymerization form NFTs which cause neurotoxicity and reduce synapses
What is the CV hypothesis?
Amyloid beta reduces cerebral blood flow which promotes amyloid beta production
Where is APOE mainly expressed/
Astrocytes
What is the pathophyisology of APOE?
Enhance amyloid deposition
Impedes Amyloid beta clearance
increased microgliosis
enhanced neuroinflammatory cytokine release
What are 2 infections that can lead to inflammation of the brain and cause AD?
Human herpes virus
Porphyromomas gingivalis
What does HHV-6 increase in the brain?
Amyloid beta precipitation & neuronal loss
What does P. gingivalis cause?
Activation of the complement pathway in the brain -> neuroinflammation
What does intracerebral infection lead to?
Induce Abeta fibrillization as an antimicrobial defence mechanisms
What do chronic infections cause?
Accumulation of amyloid plaques & NFT
What does HSV-1 cause in the brain?
Activation of the inflammatory response
What 2 neuroimmune activations are prominent in AD?
Reactive astrogliosis
microgliosis
What are SNPs thought to be involved in?
Microglial function
What 8 immune-related SNPs involved in AD?
TREM2
CR1
SHIP1
BIN1
CD33
PICALM
CLU
MSA4
What endocrine disorder is related to AD?
T2DM
What is the role g=of glucagon-like peptide 1?
Normalizes insulin signalling & is involved in neuronal activites & brain functions
what happens if there is a lack of GLP-1 receptors?
Affects synaptic plasticity & cognitive processes
What are 4 steps of T2DM that lead to AD?
- high free fatty acids
- BBB permeabilization
- Glial-mediated brain inflammation
- neuronal insulin resistance, ER-stress, synaptic failure
