By Makoto Ishii, MD, PhD
Assistant Professor of Neuroscience and Neurology, Feil Family Brain and Mind Research Institute, Department of Neurology, Weill Cornell Medical College
SYNOPSIS: Alterations in cerebrovascular insulin receptor isoform levels were associated with Alzheimer’s disease pathology and caused deficits in insulin signaling at the level of the blood-brain barrier.
SOURCE: Leclerc M, Bourassa P, Tremblay C, et al. Cerebrovascular insulin receptors are defective in Alzheimer’s disease. Brain 2023;146:75-90.
It is possible insulin signaling dysfunction in the brain or brain insulin resistance is a key contributor to the pathogenesis of Alzheimer’s disease (AD). Exogenous insulin treatment has been shown to improve memory function in AD mouse models, but more research is needed. Although overcoming brain insulin resistance in AD continues to be an active area of research with strong therapeutic potential, there remain significant gaps in our knowledge about the role of insulin in AD.
Previously, brain insulin resistance in AD was believed to be primarily caused by dysfunction of insulin signaling in neurons. In this study, Leclerc et al challenged this notion and hypothesized that brain insulin resistance in AD could be the result of defective insulin receptors (INSR) in the blood-brain barrier (BBB). They set out to test this hypothesis using post-mortem human brains from the Rush Religious Orders Study and in 3×Tg mice, a well-characterized transgenic mouse model of amyloid-beta and tau pathology.
First, the authors extracted microvessels from parietal cortex samples. They found INSR including the alpha (extracellular) and the beta (intracellular) chains were significantly enriched in microvessels compared to microvessel-depleted parenchymal fractions. Since INSR alpha has a short (A) and long (B) isoform, with higher INSR alpha-A/B ratio considered a molecular index of insulin resistance in peripheral tissues, the authors examined the specific isoforms of INSR alpha. Lower levels of INSR alpha-B were found in the cerebral microvessels, resulting in a higher INSR alpha-A/B ratio in AD compared to control brains.
Interestingly, lower levels of microvessel INSR alpha-B were associated with worse AD pathology and ante-mortem cognitive function. Furthermore, in the cerebral microvessels, INSR alpha-B levels were inversely correlated with proteins involved in amyloid-beta production and positively correlated with those involved in amyloid-beta degradation.
Next, the authors investigated the brains of 3×Tg and non-Tg control mice at various ages and found an age-related trend toward lower levels of microvessel INSR alpha-B in 3×Tg mice when compared to non-Tg mice. By age 18 months, 3×Tg mice recorded significantly lower levels of INSR alpha-B in the brain microvessels. To test whether insulin could be transported across the BBB and whether insulin could activate the INSR in the BBB, exogenous insulin was infused into the carotid arteries of the 3×Tg and non-Tg control mice. There was little evidence to support insulin being transported across the BBB through cerebral microvessel INSR in both 3×Tg and non-Tg mice; however, insulin infused into the carotid arteries could activate insulin signaling in the non-Tg mice but was blunted in the 3×Tg mice, suggesting AD pathology caused insulin resistance at the level of the BBB.
Finally, since there was a strong inverse correlation between beta-secretase 1 (BACE1), an enzyme that cleaves amyloid precursor protein (APP) to produce APP beta-CTF, the precursor to the pathogenic amyloid-beta peptides, and INSR in the cerebral microvessels, the authors postulated BACE1 protease activity could result in lower cerebral microvessel levels of INSR. Supporting this possibility, APP beta-CTF was inversely associated with microvessel levels of INSR alpha-B in human post-mortem brains.
COMMENTARY
This study makes an important contribution to our understanding of the role of insulin and INSR in AD by identifying lower cerebrovascular levels of INSR alpha-B as a possible key mechanistic link between vascular and metabolic contributions to AD pathogenesis. The major strengths of this study included the use of well-characterized post-mortem brain samples, complemented by key mechanistic studies in an established transgenic mouse model of AD.
Although the findings from this study are of significant interest, several of the conclusions remain speculative, requiring additional investigations. First, while the pancreas produces circulating insulin, the results from this study do not exclude insulin being synthesized centrally, nor did the authors address circulating insulin entering the central nervous system through other means, including circumventricular organs that lack a BBB, such as the hypothalamus.
Second, the exact cell types in the BBB that are involved in insulin signaling are unclear. Third, the pathophysiological relevance of insulin signaling dysfunction in the BBB is unknown. Does this contribute to decreased cerebral glucose uptake? Is this important for inflammation or other downstream pathways critical for AD pathogenesis? Fourth, what causes the selective decrease in INSR alpha-B levels in the cerebral microvessels? The authors hypothesized BACE1 cleaves INSR in the cerebral microvessels; however, the evidence presented is correlative in nature.
Follow-up studies are needed to validate these findings in additional human AD study populations. Other researchers should perform detailed mechanistic studies in mouse models to elucidate the importance of insulin signaling in the BBB and try to identify the pathological processes underlying how INSR alpha-B is specifically altered in the BBB during AD.
Despite the need for additional studies to address these and other open questions, the results from this exciting study have identified insulin resistance at the level of the BBB as a possible novel mechanism in the pathogenesis of AD and restoring insulin signaling in the BBB as a potential new therapeutic target in AD.
Alterations in cerebrovascular insulin receptor isoform levels were associated with Alzheimer’s disease pathology and caused deficits in insulin signaling at the level of the blood-brain barrier.
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