Glucose deficit triggers tau pathology and synaptic dysfunction in a tauopathy mouse model

Abstract

Clinical investigations have highlighted a biological link between reduced brain glucose metabolism and Alzheimer's disease (AD). Previous studies showed that glucose deprivation may influence amyloid beta formation in vivo but no data are available on the effect that this condition might have on tau protein metabolism. In the current paper, we investigated the effect of glucose deficit on tau phosphorylation, memory and learning, and synaptic function in a transgenic mouse model of tauopathy, the h-tau mice. Compared with controls, h-tau mice with brain glucose deficit showed significant memory impairments, reduction of synaptic long-term potentiation, increased tau phosphorylation, which was mediated by the activation of P38 MAPK Kinase pathway. We believe our studies demonstrate for the first time that reduced glucose availability in the central nervous system directly triggers behavioral deficits by promoting the development of tau neuropathology and synaptic dysfunction. Since restoring brain glucose levels and metabolism could afford the opportunity to positively influence the entire AD phenotype, this approach should be considered as a novel and viable therapy for preventing and/or halting the disease progression.

The vicious circle of hypometabolism in neurodegenerative diseases: Ways and mechanisms of metabolic correction

“…At the same time, the major genetic risk factors for sporadic AD, APOE ε4 allele (Liu et al, ; Zlokovic, ), and TREM2 mutations (Guerreiro et al, ; Jonsson et al, ), and a‐synuclein gene, MAPT, LRRK2, and GBA for PD (Deleidi and Gasser, ; Kalinderi et al, ) also lead to neurovascular dysfunction and neuro‐inflammation. Downstream molecular outcomes of these pathologies are, in particular: for AD, the upregulation of beta‐secretase 1 (BACE1), amyloid‐beta (Aβ) overproduction (Cirrito et al, ; Koike et al, ; O'Connor et al, ; Sun et al, ; Tamagno et al, ; Velliquette et al, ; Zhao et al, ), as well as promotion of tauopathy (Lauretti et al, ); and accumulation and aggregation of alpha‐synuclein in PD (Athauda and Foltynie, ; Jiang et al, )—suggesting that energy deficiency precedes toxic peptide overproduction so commonly thought as the defining pathology for these diseases, with its resulting neurotoxicity.…”

Advance of sporadic Alzheimer's disease animal models

“…Inhibition of PI3K and AKT also activates the glycogen synthase‐3β which promotes the Aβ accumulation and Tau hyperphosphorylation, in turn, leading to the degeneration of synapse and even neurons . In addition, glucose deficit in the brain could activate the p38 mitogen‐activated protein kinase pathway, cause memory impairments, synapse dysfunction and increase the level of Tau phosphorylation . On the basis of the observations, scientists have established the sAD animal models induced by STZ.…”

“…47 In addition, glucose deficit in the brain could activate the p38 mitogen-activated protein kinase pathway, cause memory impairments, synapse dysfunction and increase the level of Tau phosphorylation. 48 On the basis of the observations, scientists have established the sAD animal models induced by STZ.…”

Kinetic and thermodynamic study of beta-Boswellic acid interaction with Tau protein investigated by surface plasmon resonance and molecular modeling methods

“…16 Clinical investigations have highlighted a biological link between reduced brain glucose metabolism and AD. 17 Diabetes and insulin resistance are strong risk factors for cognitive decline and AD. 18,19 The effect of glucose on tau aggregation both via interfering in Tau phosphorylation, 20 Tau cleavage and Tau glycation 17,21 have been considered as probable mechanisms in crosstalk between AD and diabetes.…”