Syndecans in Alzheimer's disease: pathogenetic mechanisms and potential therapeutic targets

Abstract

With increasing age, humans become more susceptible to the onset of neurodegenerative diseases (NDs), and among these, Alzheimer’s disease (AD) is the most frequent (Nicoletti et al., 2023). NDs are primarily characterized by neuronal loss and atrophy, but also by lesions involving the cerebral and/or cardiovascular system (Balistreri, 2021). Lesions such as macro-infarcts, microinfarcts, hemorrhages, white matter lesions, atherosclerosis, and arteriolosclerosis have also been significantly described in the preclinical stages of cognitive impairment characterizing NDs (Mariani et al., 2007). Vascular lesions are described as being characterized by the lifelong accumulation of abnormally activated inflammatory cells and microglia in both brain tissue and vessel walls. This leads to a reduction in cerebral blood flow, causing insufficient energy to the neurons, particularly under conditions of increased cerebral energy demand or vasospasm (Balistreri, 2021). This alteration causes ischemia-induced neuronal apoptosis and necrosis, which can damage brain tissue and cause a range of functional symptoms. In addition, lesions of the inner vessel wall cause endothelial dysfunction, also characterized by alterations in the glycocalyx, which contribute both to the disruption of the blood–brain barrier (BBB) and further reduce cerebral blood flow, causing further damage to neurons with further infiltration of inflammatory cells. All this leads, like a vicious circle, to further neuronal damage with subsequent cortical atrophy and the onset of NDs, first and foremost AD (Balistreri, 2021). This growing evidence suggests the relevance of the vascular role in cognitive impairment and dementia, which needs to be further investigated. Accordingly, we have recently illustrated in a narrative review that the endothelium dysfunction, as well as the dysfunction of its glycocalyx and the related cellular and molecular mechanisms, represent one of the main pathological processes in the onset of NDs (Balistreri et al., 2024). Endothelial cells are, in fact, essential components of the stroma of all tissues and organs, as well as the neurovascular unit (NVU) and BBB. In the latter, endothelial cells, together with microglia cells regulate the transport of nutrients and toxins in the brain, but dysfunctional endothelial cells can also evocate brain inflammation (Balistreri and Monastero, 2023).