Reduction of advanced tau-mediated memory deficits by the MAP kinase p38γ.
Acta Neuropathol
; 140(3): 279-294, 2020 09.
Article
in En
| MEDLINE
| ID: mdl-32725265
ABSTRACT
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-ß (Aß) in mouse models. The post-synaptic mitogen-activated protein (MAP) kinase p38γ mediates this site-specific phosphorylation on tau at Threonine-205 (T205). Using a gene therapeutic approach, we draw on this neuroprotective mechanism to improve memory in two Aß-dependent mouse models of AD at stages when advanced memory deficits are present. Increasing activity of post-synaptic kinase p38γ that targets T205 in tau reduced memory deficits in symptomatic Aß-induced AD models. Reconstitution experiments with wildtype human tau or phosphorylation-deficient tauT205A showed that T205 modification is critical for downstream effects of p38γ that prevent memory impairment in APP-transgenic mice. Furthermore, genome editing of the T205 codon in the murine Mapt gene showed that this single side chain in endogenous tau critically modulates memory deficits in APP-transgenic Alzheimer's mice. Ablating the protective effect of p38γ activity by genetic p38γ deletion in a tau transgenic mouse model that expresses non-pathogenic tau rendered tau toxic and resulted in impaired memory function in the absence of human Aß. Thus, we propose that modulating neuronal p38γ activity serves as an intrinsic tau-dependent therapeutic approach to augment compromised cognition in advanced dementia.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Tau Proteins
/
Cognition Disorders
/
Alzheimer Disease
/
Memory Disorders
Limits:
Animals
Language:
En
Journal:
Acta Neuropathol
Year:
2020
Document type:
Article
Affiliation country:
Australia