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.
Highlights
Alzheimer’s disease (AD) and related tauopathies are neurodegenerative disorders pathologically defined by the presence of abundant and highly phosphorylated forms of the microtubuleassociated tau protein which later aggregates into fibrils and forms the neurofibrillary tangles (NFTs).[1]
Consistent data have established a link between systemic metabolic dysfunction, such as diabetes, and dementing disorders, suggesting that their recently observed significant increase in incidence could be in part justified by the worldwide dramatic rise in insulin resistance, obesity and diabetes.[20]
It is of interest that together with human studies, the investigations using these models have all convened on a common final point: dysregulated glucose levels and impaired energy metabolism secondary to reduced glucose utilization are a clinical feature of AD and important contributors to its pathogenesis by activating the unfolded protein response, increasing Aβ formation and deposition and, in extreme cases, resulting in neuronal death.[22,23]
Summary
Alzheimer’s disease (AD) and related tauopathies are neurodegenerative disorders pathologically defined by the presence of abundant and highly phosphorylated forms of the microtubuleassociated tau protein which later aggregates into fibrils and forms the neurofibrillary tangles (NFTs).[1]. Glucose deprivation can occur in a variety of conditions including cerebral ischemia, aging and neurodegenerative diseases.[6,7] Interestingly, positron emission tomography imaging studies have shown that glucose utilization is lower in AD than in age-matched healthy control brains.[8] In support to this observation, previous studies have demonstrated that in the transgenic mice Tg2576 (overexpressing the Swedish mutant of human APP), energy metabolism inhibition causes a post-transcriptional increase in BACE‐1 levels, which leads to elevated Aβ formation and deposition.[9] On the other hand, we have previously reported that in response to glucose deprivation neuronal cells manifest an increase in tau phosphorylation via the activation of the P38 MAPK pathway.[10] This in vitro observation supported the novel hypothesis that energy deprivation may have a role in the development of tau neuropathology, the second most important hallmark lesion of the AD brain. To the best of our knowledge, so far no data are available supporting these in vitro findings and their functional significance by demonstrating that a condition of glucose deprivation by increasing tau phosphorylation will result in memory deficit and synaptic dysfunction in vivo
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