Molecular Mechanisms Underlying Neuroprotective Effect of Intranasal Administration of Human Hsp70 in Mouse Model of Alzheimer’s Disease

Abstract

Heat shock protein 70, encoded by the HSPA1A gene in humans, is a key component of the machinery that protects neuronal cells from various stress conditions and whose production significantly declines during the course of aging and as a result of several neurodegenerative diseases. Herein, we investigated whether sub-chronic intranasal administration of exogenous Hsp70 (eHsp70) exerts a neuroprotective effect on the temporal cortex and areas of the hippocampus in transgenic 5XFAD mice, a model of Alzheimer's disease. The quantitative analysis of neuronal pathologies in the compared groups, transgenic (Tg) versus non-transgenic (nTg), revealed high level of abnormalities in the brains of transgenic mice. Treatment with human recombinant Hsp70 had profound rejuvenation effect on both neuronal morphology and functional state in the temporal cortex and hippocampal regions in transgenic mice. Hsp70 administration had a smaller, but still significant, effect on the functional state of neurons in non-transgenic mice as well. Using deep sequencing, we identified multiple differentially expressed genes (DEGs) in the hippocampus of transgenic and non-transgenic mice. Furthermore, this analysis demonstrated that eHsp70 administration strongly modulates the spectrum of DEGs in transgenic animals, reverting to a pattern similar to that observed in non-transgenic age-matched mice, which included upregulation of genes responsible for amine transport, transmission of nerve impulses and other pathways that are impaired in 5XFAD mice. Overall, our data indicate that Hsp70 treatment may be an effective therapeutic against old age diseases of the Alzheimer's type.

Hippocampal Impairment Triggered by Long-Term Lead Exposure from Adolescence to Adulthood in Rats: Insights from Molecular to Functional Levels

“…Both members were found upregulated in our proteomic analysis, suggesting a mechanism of protection of hippocampal cells against long-term Pb exposure. On the other hand, we observed downregulation of HSP70 1A and 1B (P0DMW0 and P0DMW1, respectively) that are associated with the cytoskeleton protection and neuroprotection against incorrectly folded proteins in Alzheimer's and Parkinson's diseases [28,29]. Moreover, HSP are also involved in apoptosis prevention and oxidative stress responsiveness signaling [27].…”

Near Infrared Light Treatment Reduces Synaptic Levels of Toxic Tau Oligomers in Two Transgenic Mouse Models of Human Tauopathies

“…The systemic reduction of both total and oligomeric tau in NIR light-treated hTau mice that we report here suggests that NIR light initiates mechanisms that contribute to the regulation and the clearance of tau. In the current study, we investigated the chaperone HSP70 and proteins involved the induction of autophagy as two known pathways that have been reported to promote the degradation of dysfunctional tau [ 2 , 39 ]. The HSP70 family of proteins are chaperones that are involved in the refolding and shuttling of dysfunctional proteins to degradation pathways [ 40 ].…”

“…There is extensive literature describing the intimate relationship between inducible HSP70 and the clearance of the toxic tau proteins. Particularly, evidence demonstrates the reduction of aggregated tau after stimulating the activity of or overexpressing endogenous inducible HSP70 or following administration of exogenous inducible HSP70 [ 39 , 41 , 42 ]. On the other hand, an opposite correlation exists between tau and heat shock cognate 70 (HSC70), a constitutively expressed member of the HSP70 family, whereby HSC70 overexpression slows the clearance of misfolded tau deposition [ 24 ].…”

Multimodal single-cell/nucleus RNA-sequencing data analysis uncovers molecular networks between disease-associated microglia and astrocytes with implications for drug repurposing in Alzheimer’s disease

“…Inhibiting HPSE2 activates HPSE to decrease neurotoxicity and reduce tau hyperphosphorylation in AD 51 . Both heat shock 70 kDa protein 1A (HSPA1A 52 ) and heat shock 70 kDa protein 1B (HSPA1B 53 ) regulated oxide stress in either mouse model or human AD brains, suggesting their crucial role in AD biology and possible treatment approaches.…”