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 are associated with Alzheimer’s disease pathology and cause 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.
Accumulating evidence supports insulin signaling dysfunction in the brain or brain insulin resistance as 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; however, relatively small clinical trials using intranasal insulin have had mixed results. 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 present study, LeClerc and colleagues 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 3xTg mice, a well-characterized transgenic mouse model of amyloid-beta (Aβ) and tau pathology.
First, using post-mortem brains from the Rush Religious Orders Study, the authors extracted microvessels from parietal cortex samples. They found that INSR including the α (extracellular) and the β (intracellular) chains were significantly enriched in microvessels compared to microvessel-depleted parenchymal fractions.
Since INSRα has a short (A) and long (B) isoform with higher INSRα-A/B ratio considered a molecular index of insulin resistance in peripheral tissues, the authors next examined the specific isoforms of INSRα. Lower levels of INSRα-B were found in the cerebral microvessels resulting in a higher INSRα-A/B ratio in AD compared to control brains. Interestingly, lower levels of microvessel INSRα-B were associated with worse AD pathology and ante-mortem cognitive function. Furthermore, in the cerebral microvessels, INSRα-B levels were inversely correlated with proteins involved in Aβ production and positively correlated with those involved in Aβ degradation.
Next, the authors investigated the brains of 3xTg and non-Tg control mice at various ages and found an age-related trend toward decreased levels of microvessel INSRα-B in 3xTg mice when compared to non-Tg mice. By 18 months of age, 3xTg mice had significantly lower levels of INSRα-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 3xTg and non-Tg control mice. There was little evidence to support insulin being transported across the BBB through cerebral microvessel INSR in both 3xTg 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 3xTg mice, suggesting that AD pathology caused insulin resistance at the level of the BBB.
Finally, since there was a strong inverse correlation between β-secretase 1 (BACE1), an enzyme that cleaves amyloid precursor protein (APP) to produce APPβ-CTF, the precursor to the pathogenic Aβ peptides, and INSR in the cerebral microvessels, it was postulated that BACE1 protease activity could result in lower cerebral microvessel levels of INSR. Supporting this possibility, APPβ-CTF was inversely associated with microvessel levels of INSRα-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 decreased cerebrovascular levels of INSRα-B as a possible key mechanistic link between vascular and metabolic contributions to AD pathogenesis. Major strengths of this study include the use of well-characterized post-mortem brain samples from the Rush Order of Religious Study that are 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 made by the authors remain speculative, requiring additional investigations. First, while circulating insulin is produced in the pancreas, the results from this study do not exclude insulin being synthesized centrally, nor does it 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 not clear. Third, the pathophysiological relevance of insulin signaling dysfunction in the BBB is not known. 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 INSRα-B levels in the cerebral microvessels? The authors hypothesized that BACE1 cleaves INSR in the cerebral microvessels; however, the evidence presented is correlative in nature.
Clearly, follow-up studies are needed to validate these findings in additional human AD study populations and to perform detailed mechanistic studies in mouse models to elucidate the importance of insulin signaling in the BBB and to identify the pathological processes underlying how INSRα-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.
