Skip to main content

Memory and learning in Alzheimer's disease: involvement of amyloid precursor protein and tau in function and dysfunction of the hippocampal formation

Final Activity Report Summary - COGNOS.AD (Memory and learning in Alzheimer's disease: involvement of amyloid precursor protein and tau in function and dysfunction of the hippocampal formation)

Protein tau is a major microtubule-associated protein in the vertebrate nervous system. Differential phosphorylation and isoform expression of tau are believed to regulate the assembly and stabilisation of microtubuli. Alzheimer's disease, frontotemporal dementia (FTD) and many other neurodegenerative diseases that manifest late in life are characterised by neurofibrillar inclusions of highly phosphorylated protein tau.

In this project, tau and two of its most important kinases were characterised in different contexts and several new functions were determined. Expression of tau was shown to suppress proliferation, promote neuronal differentiation and restore neurite and axonal outgrowth in the hippocampus of a tau knockin-knockout mouse model. Overexpression of tau kinase cdk5 activator p25 resulted in gliosis. As astroglia and microglia fuelled inflammation, rapid neurodegeneration lead to hippocamapal sclerosis.

Not only GSK3-beta, but also its isoenzyme GSK3-alpha were shown to increase tau phosphorylation. Another effect of GSK3-beta over-expression was the impeded transport of synaptically active a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors to the cell surface after glycine stimulation, indicating negative effects on long-term potentiation and cognition.