Abstract
Diabetes is a risk factor for Alzheimer’s disease (AD) in humans. Branched-chain amino acids (BCAAs, namely valine, leucine, and isoleucine) metabolic defect is observed in human diabetes, which is associated with insulin resistance. But whether BCAAs connect diabetes and AD remains unknown. Here, we show that BCAA metabolic defect may be one of the drivers of AD. BCAA levels were increased in the blood in human patients and mice with diabetes or AD. BCAA-enriched diet promoted the development of AD in mice as evidenced by the behavior and pathological analysis. Branched-chain amino acid transaminase 1 and 2 (BCAT1 and BCAT2) are the two enzymes for the first step metabolism of BCAAs by catalyzing BCAAs to generate branched-chain ketoacids. The expression of Bcat1 but not Bcat2 was significantly down-regulated in the brain tissues of diabetic, aged, and AD mice. Leucine up-regulated the phosphorylation of Tau but not affected the accumulation of amyloid β in the brain tissues or isolated neurons. In addition, knockdown of the expression of Bcat1, which would result in the accumulation of BCAAs, led to the same phenotype as BCAAs supplement in neurons. Interestingly, leucine supplement or Bcat1 knockdown promoted the activation of the mTOR signaling in the brains of AD mice or neurons. Subsequently, mTOR was critically involved in leucine and Bcat1 knockdown-mediated phosphorylation of Tau. Taken together, our findings demonstrated that diabetes-related BCAA accumulation in the brain tissues led to the phosphorylation of Tau and, subsequently, the development of diabetes-related AD.
Highlights
Alzheimer’s disease (AD) is one of the most prevalent causes of dementia
We aimed to investigate whether branched-chain amino acid (BCAA) are a factor connecting diabetes and AD
The results showed that BCAA levels were increased in the serum of patients with type 2 diabetes (n=10; 6 males and 4 females; mean age = 69.1 years; 4 with and six without Alzheimer’s disease) compared with aged-matched healthy donors (n=6; 3 males and 3 females; mean age = 67.7 years; without AD) (Figure 1A)
Summary
Alzheimer’s disease (AD) is one of the most prevalent causes of dementia. Amyloid β42 and phosphorylated Tau proteins are established as core cerebrospinal biomarkers for AD [1]. Treatment strategies targeted at reducing amyloids have failed to reverse cognitive symptoms. AD is fundamentally a metabolic disease with molecular and biochemical features that correspond with diabetes and other peripheral insulin resistance disorders [4]. Continued elucidation of the links between metabolic disorders and neural dysfunction promises to foster the development of effective therapeutic strategies [6]. Diabetes is connected to AD clinically, and experimental molecular and biochemical links are limited. MTOR was already well known as a regulator of growth and protein translation, c 2018 The Author(s).
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