Experimental diabetes mellitus exacerbates tau pathology in a transgenic mouse model of Alzheimer's disease.
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 beta-amyloid (Abeta) and tau, two proteins that form Abeta 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.
Ke
Yazi D
YD
Alzheimer's and Parkinson's Disease Laboratory, Brain & Mind Research Institute, University of Sydney, Sydney, Australia.
Delerue
Fabien
F
Gladbach
Amadeus
A
Götz
Jürgen
J
Ittner
Lars M
LM
D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015897:Comorbidity; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism*; D004195:Disease Models, Animal; D005561:Formates / Q000737:chemistry; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010766:Phosphorylation; D012521:Sarcosine / Q000031:analogs & derivatives / Q000737:chemistry; D013997:Time Factors; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism*
D001786:Blood Glucose; D005561:Formates; D016875:tau Proteins; C030544:formic acid; C025231:sarkosyl; D012521:Sarcosine