Abstract
The microtubule-associated protein tau pathologically accumulates and aggregates in Alzheimer’s disease (AD) and other tauopathies, leading to cognitive dysfunction and neuronal loss. Molecular chaperones, like small heat-shock proteins (sHsps), can help deter the accumulation of misfolded proteins, such as tau. Here, we tested the hypothesis that the overexpression of wild-type Hsp22 (wtHsp22) and its phosphomimetic (S24,57D) Hsp22 mutant (mtHsp22) could slow tau accumulation and preserve memory in a murine model of tauopathy, rTg4510. Our results show that Hsp22 protected against deficits in synaptic plasticity and cognition in the tauopathic brain. However, we did not detect a significant change in tau phosphorylation or levels in these mice. This led us to hypothesize that the functional benefit was realized through the restoration of dysfunctional pathways in hippocampi of tau transgenic mice since no significant benefit was measured in non-transgenic mice expressing wtHsp22 or mtHsp22. To identify these pathways, we performed mass spectrometry of tissue lysates from the injection site. Overall, our data reveal that Hsp22 overexpression in neurons promotes synaptic plasticity by regulating canonical pathways and upstream regulators that have been characterized as potential AD markers and synaptogenesis regulators, like EIF4E and NFKBIA.
Highlights
Tau is a microtubule-associated protein that has been linked to multiple neurodegenerative diseases, with the most prevalent being Alzheimer’s disease (AD) [1]
We focused on canonical pathways that were dysregulated in the GFPinjected rTg4510 compared to non-transgenic mice and restored by wildtype Hsp22 (wtHsp22) or mutant Hsp22 (mtHsp22) overexpression
We found that overexpressing Hsp22 in tau transgenic mice improved cognition and synaptic plasticity
Summary
Tau is a microtubule-associated protein that has been linked to multiple neurodegenerative diseases, with the most prevalent being Alzheimer’s disease (AD) [1]. Instead of ATP, the activity of sHsps is regulated through phosphorylation of their N-terminal domain through stress-activated kinases [9], which can be simulated by phosphomimetic substitutions of corresponding amino acids [10]. These sHsps have been shown to have increased expression with aging, to directly interact with autophagy-related proteins, and to form complexes that help regulate aberrant proteins in the cell [11–13]. The closely related chaperone Hsp, encoded by the HSPB8 gene, has been shown to reduce Aβ and α-synuclein aggregation and has a protective role during aging [16,19,20]. Hsp phosphorylation or mimetic mutations can impair the chaperone activity of Hsp, as previously demonstrated by reduced inhibition of insulin and rhodanese aggregation [21]. Cognitive function, synaptic plasticity, and neuronal health in the brains of tau transgenic mice
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