Abstract
Diabetes mellitus (DM) is characterized by hyperglycemia caused by a lack of insulin, insulin resistance, or both. There is increasing evidence that insulin also plays a role in Alzheimer's disease (AD) as it is involved in the metabolism of β-amyloid (Aβ) and tau, two proteins that form Aβ plaques and neurofibrillary tangles (NFTs), respectively, the hallmark lesions in AD. Here, we examined the effects of experimental DM on a pre-existing tau pathology in the pR5 transgenic mouse strain that is characterized by NFTs. pR5 mice express P301L mutant human tau that is associated with dementia. Experimental DM was induced by administration of streptozotocin (STZ), which causes insulin deficiency. We determined phosphorylation of tau, using immunohistochemistry and Western blotting. Solubility of tau was determined upon extraction with sarkosyl and formic acid, and Gallyas silver staining was employed to reveal NFTs. Insulin depletion by STZ administration in six months-old non-transgenic mice causes increased tau phosphorylation, without its deposition or NFT formation. In contrast, in pR5 mice this results in massive deposition of hyperphosphorylated, insoluble tau. Furthermore, they develop a pronounced tau-histopathology, including NFTs at this early age, while the pathology in sham-treated pR5 mice is moderate. Whereas experimental DM did not result in deposition of hyperphosphorylated tau in non-transgenic mice, a predisposition to develop a tau pathology in young pR5 mice was both sufficient and necessary to exacerbate tau deposition and NFT formation. Hence, DM can accelerate onset and increase severity of disease in individuals with a predisposition to developing tau pathology.
Highlights
Alzheimer’s disease (AD) is a devastating progressive neurodegenerative disease affecting more than 15 million people worldwide [1]
We addressed whether metabolic changes present in Diabetes mellitus (DM) affect tau pathology, by inducing experimental DM in a transgenic model of AD
We showed that depletion of insulin upon STZ injection and chronically increased blood glucose levels causes hyperphosphorylation of tau, a protein associated with AD
Summary
Alzheimer’s disease (AD) is a devastating progressive neurodegenerative disease affecting more than 15 million people worldwide [1]. It is characterized by neuronal loss associated with a progressive decline in memory and other cognitive functions, resulting in dementia. In the AD brain, the b-amyloid (Ab) peptide and the microtubule-associated protein tau undergo changes in their tertiary structures leading to self-association and deposition. Tau contains multiple phosphorylation sites, that are hyperphosphorylated under pathological conditions, such as AD and FTLD [6]. Deposition of hyperphosphorylated tau in the absence of an overt Ab pathology characterizes approximately half of all FTLD cases [2]. Along with others, expressed mutant human tau in transgenic mice that recapitulate major aspects of the human disease (reviewed in [9])
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