LC 6 - taupathies Flashcards
1
Q
Tau and neurodegeneration
A
- Tau is the constituent of the neurofibrillary tangles, which is a diagnostically characteristic lesion of AD brains
- Tau contributes to AD via hyperphosphorylation
o Loss of function of normal tau (impaired axonal transport)
o Toxic effects of ptau - There are various tauopathies: AD, downs, picks, FTD (tau with no Abeta), etc.
2
Q
spreading of tau accumulation
A
braak stages:
1. entorhinal
2. limbic
3. cortext
- prion-like spreading/seeding of aggregates
- spreading correlates strongly with disease progression
3
Q
amyloid cascade and tau
A
- altered APP processing
- Ab42 production
- neurotoxic effects of oligomeric and protofibrillary Abeta on synapses
- inflammation - micorglia and astrocytes
- oxadative injury and altered ion homeostasis
- changes in intracellular signalling
- tau hyperphosphorylation
- NFT formation
- extensive neuronal dysfunction
- dementia
4
Q
tau-directed therapies: goals
A
-Rescue of Tau loss of function
-Inhibition of Tau phosphorylation
-Inhibition of other post-translational modifications
-Inhibition of Tau-aggregation/oligomerisation
-Immunisation therapy directed at Tau and Tau*
-Selective clearance of abnormal Tau forms
-Ubiquitin-proteasome (refolding pathways)
-Autophagic-lysosomal clearance pathways
-Inhibition of spreading of Tau-pathology
5
Q
therapeutic strategies
A
- Loss of function compensation
- Tau aggregates inhibitors (beta-sheets)
- Inhibition of Tau kinases (GSK3beta)
- Immunotherapy (hard since intracellular, can prevent spreading though)
6
Q
Antisense Oligonucleuotides in neurodegeneration
A
- Breakthrough in neurodegeneration perhaps
- Clearance of soluble Tau from cells but not sure if cognition improvements follows the reduction of the biomarker reduction
- Might be used in combo with another treatment to treat AD: multi-targeted therapies
o Which combo will depend on the individual patients subtyping: personalised medicine
