Tau target identification reveals NSF-dependent effects on AMPA receptor trafficking and memory formation.

Microtubule-associated protein tau is a central factor in Alzheimer's disease and other tauopathies. However, the physiological functions of tau are unclear. Here, we used proximity-labelling proteomics to chart tau interactomes in primary neurons and mouse brains in vivo.

High Level Forebrain Expression of Active Tau Kinase p38γ Exacerbates Cognitive Dysfunction in Aged APP-transgenic Alzheimer's Mice.

Persistent improvement of cognitive deficits in Alzheimer's disease (AD), a common form of dementia, is an unattained therapeutic objective. Gene therapy holds promise for treatment of familial and sporadic forms of AD. p38γ, a member of the p38 mitogen-activated protein (MAP) kinase family, inhibits amyloid-β toxicity through regulation of tau phosphorylation.

Interaction between the guanylate kinase domain of PSD-95 and the proline-rich region and microtubule binding repeats 2 and 3 of tau.

The microtubule-associated protein tau is a key factor in neurodegenerative proteinopathies and is predominantly found in neuronal axons. However, somatodendritic localization of tau occurs in a subset of pathological and physiological tau. Dendritic tau can localize to post-synapses where it interacts with proteins of the post-synaptic density (PSD) protein PSD-95, a membrane-associated guanylate kinase (MAGUK) scaffold factor for organization of protein complexes within the PSD, to mediate downstream signals.

Functions of p38 MAP Kinases in the Central Nervous System.

Mitogen-activated protein (MAP) kinases are a central component in signaling networks in a multitude of mammalian cell types. This review covers recent advances on specific functions of p38 MAP kinases in cells of the central nervous system. Unique and specific functions of the four mammalian p38 kinases are found in all major cell types in the brain.

Reduction of advanced tau-mediated memory deficits by the MAP kinase p38γ.

Hyperphosphorylation of the neuronal tau protein contributes to Alzheimer's disease (AD) by promoting tau pathology and neuronal and cognitive deficits. In contrast, we have previously shown that site-specific tau phosphorylation can inhibit toxic signals induced by amyloid-β (Aβ) in mouse models. The post-synaptic mitogen-activated protein (MAP) kinase p38γ mediates this site-specific phosphorylation on tau at Threonine-205 (T205).

Mapping p38α mitogen-activated protein kinase signaling by proximity-dependent labeling.

Mitogen-activated protein (MAP) kinase signaling is central to multiple cellular responses and processes. MAP kinase p38α is the best characterized member of the p38 MAP kinase family. Upstream factors and downstream targets of p38α have been identified in the past by conventional methods such as coimmunoprecipitation.

CNS cell type-specific gene profiling of P301S tau transgenic mice identifies genes dysregulated by progressive tau accumulation.

The microtubule-associated protein tau undergoes aberrant modification resulting in insoluble brain deposits in various neurodegenerative diseases, including frontotemporal dementia (FTD), progressive supranuclear palsy, and corticobasal degeneration. Tau aggregates can form in different cell types of the central nervous system (CNS) but are most prevalent in neurons. We have previously recapitulated aspects of human FTD in mouse models by overexpressing mutant human tau in CNS neurons, including a P301S tau variant in TAU58/2 mice, characterized by early-onset and progressive behavioral deficits and FTD-like neuropathology.