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Ageing brain and Alzheimer (Gene mutations (gene PSEN2, gene APP, gene…
Ageing brain and Alzheimer
risk factors
lifestyle
smoking
high blood pressure
type 2 diabetes
lack of exercise
obesity
high cholesterol levels
age
genetics
Hallmarks of aging
Epigenetic alterations
Tau is more heavily acetylated
Contribute to neurodegeneration
Loss of proteostasis
Protein degradation pathway impairment
Autophagy
Ubiquitin-proteosome system
Misfolded and aggregated proteins bind to PRRs one microglia and astroglia
trigger innate immune response
release of inflammatory mediators
contribute to disease progression and severity
Gene mutations
gene PSEN2
gene APP
gene PSEN1
allele APOE e4
lead to overproduction of amyloid-ß peptide
Aging
worse executive and attentional functions
Reasoning
Cognitive flexibility
Focused and divided attention
Memory dysfunction
Episodic
Working
Short-term
structural changes
Gray matter declines linear
White matter firstly increases and than declines (U-shape)
neurofibrillary tangles
hyperphosphorylation of Tau protein
Internal transport netwerk of neurons collapses
Reduced stability of microstructures
Cooperation between neurons inhibited
Intra neuronal
senile plaques
aggregation is neurotoxic
Composed of amyloid-beta peptides
can be byproduct of senescence
Extracellular
APP is cut by beta-secretase instead of alpha-secretase
Alternations in the AD brain
Damage to the BBB
Toxins and microbes enter the brain interstitial fluid
Neuro-inflammation
Misfolded proteins (DAMPs) bind to microglia and astroglia
Altered peptides
Cholesterol: enhances plaque formation
Sphingolipids: enhance both
Phospholipids: enhance inflammation
Treatments
Statins decrease cholesterol levels
Acetylcholinesterase inhibitors -> donepezil
NMDA receptor antagonist
Treatments
Tau-targeting therapies
Statins (cholesterol reducing medication)