Abstract
There are fewer than normal glucose transporters at the blood-brain barrier (BBB) in Alzheimer’s disease (AD). When reduced expression of transporters aggravates the symptoms of AD, the transporters become a potential target of therapy. The incretin hormone GLP-1 prevents the decline of cerebral metabolic rate for glucose (CMRglc) in AD, and GLP-1 may serve to raise transporter numbers. We hypothesized that the GLP-1 analog liraglutide would prevent the decline of CMRglc in AD by raising blood-brain glucose transfer, depending on the duration of disease. We randomized 38 patients with AD to treatment with liraglutide (n = 18) or placebo (n = 20) for 6 months, and determined the blood-brain glucose transfer capacity (Tmax) in the two groups and a healthy age matched control group (n = 6). In both AD groups at baseline, Tmax estimates correlated inversely with the duration of AD, as did the estimates of CMRglc that in turn were positively correlated with cognition. The GLP-1 analog treatment, compared to placebo, highly significantly raised the Tmax estimates of cerebral cortex from 0.72 to 1.1 umol/g/min, equal to Tmax estimates in healthy volunteers. The result is consistent with the claim that GLP-1 analog treatment restores glucose transport at the BBB.
Highlights
Alzheimer’s disease (AD) is characterized by deposits of amyloid-β (Aβ) and hyperphosphorylated tau proteins that may impair neurovascular regulation, blood brain barrier (BBB) integrity[9], and expression of glucose transporters at the BBB6
Recent work in mice reveals that reduced expression of GLUT1 in the blood-brain barrier (BBB) leads to massive progression of AD neuropathology, and that GLUT1 deficiency in the endothelium initiates BBB breakdown, possibly as an early pathogenic step in the evolution of AD25
In the present analysis of findings obtained in patients with AD, we discovered a highly significant effect of the glucagon-like peptide-1 (GLP-1) analog liraglutide on the blood-brain glucose transport capacity
Summary
Alzheimer’s disease (AD) is characterized by deposits of amyloid-β (Aβ) and hyperphosphorylated tau proteins that may impair neurovascular regulation, blood brain barrier (BBB) integrity[9], and expression of glucose transporters at the BBB6. Loss of glucose transporters from the BBB is known to occur before the onset of AD symptoms[6], and PET of [18F]fluoro-2-deoxyglucose ([18F]FDG)-derived radioactivity in brain reveals progressive reduction of cerebral metabolic rate of glucose CMRglc, before detection of clinical symptoms in individuals with subsequently confirmed AD12. Uptake and metabolism[17,18,19] This means that it is possible that glucose transport across the BBB may become the rate-limiting step of glucose metabolism in AD20, the disorder in which the number of glucose transporters is known to be reduced[21,22]. Restoration of mechanisms important to the neurovascular unit by liraglutide and prevention of further neurovascular degeneration would avert the potential exacerbation of glucose transporter deficiency in AD28, in agreement with the view that glucose transport is a potentially important therapeutic target of treatment in AD6,25
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