Abstract
Alzheimer disease (AD) is the most frequent cause of dementia and up to now there is not an effective therapy to cure AD. In addition, AD onset occurs decades before the diagnosis, affecting the possibility to set up appropriate therapeutic strategies. For this reason, it is necessary to investigate the effects of risk factors, such as cardiovascular diseases, in promoting AD. AD shows not only brain dysfunction, but also alterations in peripheral tissues/organs. Indeed, it exists a reciprocal connection between brain and heart, where cardiovascular alterations participate to AD as well as AD seem to promote cardiovascular dysfunction. In addition, metabolic dysfunction promotes both cardiovascular diseases and AD. In this review, we summarize the pathways involved in the regulation of the brain-heart axis and the effect of metabolism on these pathways. We also present the studies showing the role of the gut microbiota on the brain-heart axis. Herein, we propose recent evidences of the function of Thioredoxin Interacting protein (TXNIP) in mediating the role of metabolism on the brain-heart axis. TXNIP is a key regulator of metabolism at both cellular and body level and it exerts also a pathological function in several cardiovascular diseases as well as in AD.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia characterized by progressive memory loss and cognitive decline [1]
We provide evidences that unveil the central role of Thioredoxin Interacting protein (TXNIP) in mediating the effects of metabolism in altering the brain-heart axis and in turn promoting AD
gut microbiome (GM) depleted mice fed with high-fat diet (HFD) show enhanced levels of glucagon-like peptide 1 (GLP-1), which is essential for GM depletion-induced amelioration of hypothalamus inflammation [120] through the signaling downstream GLP-1 receptor (GLP-1R) present on astrocytes [120]
Summary
Alzheimer’s disease (AD) is the most common form of dementia characterized by progressive memory loss and cognitive decline [1]. The discovery of the genes responsible for FAD contributed to the postulation of the amyloid cascade hypothesis of AD pathogenesis, which defines a linear causality between Aβ accumulation and AD pathophysiology [3]. Each drug alone or a combination of ChEIs with memantine, only modestly ameliorate the cognitive deficit in AD patients It has been developed only another drug for AD, Aduhelm (aducanumab), very recently approved by FDA [5]. It is necessary discover new therapeutic targets for AD For this reason, several studies are aimed in unveiling the role of metabolism and risk factors in AD onset and progression. Recent studies underline a connection between neurodegenerative and cardiovascular diseases, defining the so-called brain-heart axis [18]. We shed light into the potential role of Thioredoxin Interacting Protein (TXNIP)—the inhibitor of the ROS-scavenger Thioredoxin (Trx) and the regulator of glucose homeostasis [19]—as key regulator of the brain-heart axis and thereby a therapeutic target for AD, by analyzing the putative role of TXNIP in the bi-directional regulation of the brain-heart axis in AD
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