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

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).

Impairment of NVU and BBB has been shown to correlate with altered clearance of amyloid-β, tau, and α-synuclein peptides and their subsequent accumulation in the brain. Furthermore, it has been reported that damage to the NVU and BBB contributes to neuroinflammation through the release of small molecule toxins and pro-inflammatory mediators, which cross the impaired BBB, thus contributing to neuronal damage (Balistreri and Monastero, 2023). Furthermore, cardiovascular diseases, which generally cause the onset of cerebral infarctions (also with microvascular subcortical disease), are another crucial factor significantly associated with the disruption of the NVU and BBB. Finally, another crucial aspect that emerges from this complex puzzle is the hypothesis about the primordial origin of NDs. Accordingly, it has been reported that these disorders could originate during embryonic development (i.e., fetal origins of adult disease hypothesis). The latter proposes that the susceptibility of NDs is programmed in the womb, like adult cardiovascular diseases, age-related hemopoiesis, and dysimmune diseases (Balistreri et al., 2019). Specifically, it has been suggested that NDs are the result of the complex imprinting process on fetal hemogenic endothelium, from which the microglial cells originate. This imprinting is mediated by the developing placenta and epigenetic mechanisms capable of influencing the plasticity and memory of microglial cells. This fundamental role of endothelial/glycocalyx (eGCX) dysfunction in AD is becoming a subject of study of our and other groups. Here, our focus is on the role of syndecans in AD.

The Syndecans family: Emerging evidence has demonstrated the contribution of eGCX, with pleiotropic roles, in the onset and progression of NDs. eGCX dysfunction characterized by its degradation has been observed to occur in NDs, such as AD; accordingly, circulating levels of related eGCX degradation products have been proposed as AD biomarkers. In addition to their role as diagnostic biomarkers, some eGCX fragments act as pathogenic factors in disease progression thus representing potential prognostic biomarkers. This is leading to the development of pharmacological interventions and potential strategies to attenuate eGCX degradation or restore its integrity, maintaining endothelial health into adult life. Among the eGCX degradation products, the syndecans (SDCs), and heparan sulfate proteoglycans, have attracted the attention of several researchers (Balistreri et al., 2022; Balistreri, 2024). The components of the glycocalyx are glycoproteins with short acid oligosaccharides and terminal sialic acids, oligosaccharides, and heparan sulfate proteoglycans, such as SDCs, and glycosaminoglycans.

SDCs family includes four members: SDC-1, SDC-2, SDC-3, and SDC-4, consisting of a core protein modified by heparan sulfate chains. Each SDC has defined expression patterns and functions in their respective target tissues. SDC-3 is expressed in neuronal and musculoskeletal cells. SDC-3 (N-SDC or neuronal SDC) is a transmembrane protein 442 amino acid long. Analysis of SDC-3 in experimental models of inflammation and AD showed that patients with AD have overexpression of SDC-3, not only in the brain but also in the periphery (Balistreri et al., 2024). Consequently, SDC-3 could serve as a basis for the development of future AD diagnostics.

Syndecans and AD: As mentioned earlier, syndecans play an important role in neuronal development and CNS angiogenesis during embryogenesis. However, during aging overexpression of syndecans can lead to neurodegenerative processes with the formation of pathological neuronal inclusions such as amyloid plaques and neurofibrillary tangles (Hudák et al., 2022). Some preclinical studies have described the role of glycocalyx dysfunction in AD. Specifically, overexpression of SDC-3 in AD patients facilitates the endocytosis of amyloid-beta (Aβ) 1–42 and its fibrillation, thus contributing to the progression of the Aβ plaque pathology process in the brain (Hudák et al., 2022). Interestingly, the increased polymerization of Aβ appears to be mediated by the interaction between ApoE (the main susceptibility gene for sporadic AD) and SDC-3 (Balistreri et al., 2024). Central CNS inflammation constitutes one of the most relevant pathophysiological mechanisms during NDs (Balistreri and Monastero, 2023). Several data have described the key role of T- and B-cell subpopulations and microglia in AD patients (Martorana et al., 2014), as well as the increase of several mediators of inflammation during the disease (Balistreri and Monastero, 2023). Among these, tumor necrosis factor-alpha has been described as significantly elevated in plasma and CSF of AD patients. In vitro studies demonstrated an induction of SDC-3 monocytes after culture with tumor necrosis factor-alpha. Furthermore, in a transgenic mouse model of AD, peripheral monocytes showed increased expression of SDC-3, which correlated significantly with brain amyloid burden (Hudák et al., 2022). Therefore, the expression of SDC-3 in peripheral blood monocytes should be validated as a possible biomarker for the early diagnosis of AD.

Overall, there are interesting preclinical data demonstrating the involvement of SDC-3 during AD (Balistreri et al., 2024). Additionally, recent pathological data obtained in the brains of AD patients show increased expression of SDCs in the AD patient’s brain, which seems to correlate with tau- and Aβ-related pathology (Hudák et al., 2022). These data were further confirmed by another neuropathological study that showed consistent overexpression of SDC-4 in all brain areas of subjects with AD. Interestingly, this was the case for all stages of the disease (mild, moderate, and severe AD); moreover, immunohistochemistry data showed that SDC-4 was associated with the two main lesions of the disease, beta-amyloid and tau (Lorente-Gea et al., 2020; Fernández-Vega et al., 2021). Unfortunately, to date, no clinical data are available on the plasma, serum, or CSF distribution of different SDCs in AD or other NDs. Future clinical and laboratory studies should clarify the mechanisms by which SDCs modulate the precipitation and aggregation of pathological proteins during NDs. Such data will allow evaluation of the diagnostic and prognostic significance of SDCs in NDs, with considerable relevance in therapeutic settings.

Conclusions and perspectives: Thus, eGCX injury and endothelial dysfunction appear to be key factors in the onset and progression of AD. Therefore, preserving the integrity and related functions of the endothelium and its components, such as eGCX, may result in a delay of all the mechanisms, partly described above, associated with direct and indirect damage to neurons and the subsequent onset of the neurodegenerative process of AD. This evidence has led researchers to identify new approaches and therapeutic strategies to restore eGCX and its functions (Figure 1).

Figure 1.

New approaches and therapeutic strategies proposed to restore eGCX.

Created with BioRender.com. eGCX: Endothelial/glycocalyx; HA: hyaluronic acid; HS: heparan sulfate; NO: nitric oxide; PEG: polyethylene glycol.

A possible therapeutic strategy is based on reducing the shedding of eGCX components by treatment with angiopoietin-2, which, acting as an intrinsic antagonist of angiopoietin 1, prevents the anti-inflammatory signaling normally induced by angiopoietin 1 activation, and results in reduced eGCX shedding and improved survival of animal models, such as mice (Balistreri et al., 2024). Other proposed strategies to restore eGCX include restoring appropriate NO levels, as well as restoring sirtuin-1 expression levels and activity to regulate levels of antioxidants, such as N-acetylcysteine (Balistreri et al., 2024). Another potential therapeutic strategy may require the use of high molecular weight hyaluronic acid to accelerate the restoration of eGCX. Additionally, even low concentrations of albumin have also been shown to protect eGCX. An additional approach is based on targeting the Wnt signaling pathway to increase glucose clearance capacity independent of insulin secretion, and to reduce the risk of eGCX degradation (Balistreri et al., 2024).

Other possibilities consist of reprogramming eGCX by means of engineered heparan sulfate (Figure 1) or using nutraceuticals supplementation, including, for example, the administration of Arterosil and Endocalyx, consisting of polysaccharides that mimic eGCX components such as heparin and heparan sulfate (Machin et al., 2023, Balistreri et al., 2024), or of probiotics and omega-3 (Ω-3) fatty acids (Balistreri et al., 2024). Oral administration of Arterosil has been used in a limited number of preliminary studies in human patients and its localization in both arterial and venous endothelium has been observed. However, its application in human studies is limited and the results obtained are unclear. Further research is needed, especially considering that rhamnan sulfate is not a naturally occurring component in the body and may provoke intense immune responses in some individuals, limiting the benefits of Arterosil treatment. However, evidence on the efficacy of Arterosil so far is encouraging and suggests that it may become a viable drug candidate for eGCX repair in the clinical setting. With regard to Endocalyx administration, studies are limited to older mice (30 months) treated with Endocalyx for 10 weeks (Machin et al., 2023). The results obtained are encouraging. However, no clinical studies on the possible effect of Endocalyx as a therapeutic strategy for AD have been conducted so far. This necessitates the implementation of clinical trials to evaluate this therapeutic strategy.

Mixed supplementation of probiotics and Ω-3 fatty acids could be another emerging treatment to determine eGCX regeneration (Balistreri et al., 2024). Probiotic strains, such as Lactobacilli and Bifidobacteria, result in lipopolysaccharide-dependent reduction of low-grade chronic inflammation by inhibiting lipopolysaccharide binding to the CD14 receptor and thus decreasing the overall activation of NF-κβ. Ω-3 fatty acids have been shown to potentiate Bifidobacteria through unclear mechanisms, which retain lipopolysaccharide and reduce lipopolysaccharide-producing bacteria such as Enterobacteria. It has often been confirmed that Ω-3 supplementation reduces endothelial dysfunction and increases vasodilation and vessel elasticity, as well as reducing inflammatory pathways (Balistreri et al., 2024). This evidence suggests that the interactions between lipid metabolism and eGCX might be particularly relevant for further research, as well as the use of probiotics in the treatment of eGCX dysfunction.

In recent years, the combination of a healthy dietary pattern, caloric restriction, and physical activity has been used in clinical intervention studies with rather promising results (Balistreri et al., 2024). Intermittent fasting and similar dietary strategies are based on limiting the defined daily time to eat and prolonging fasting. The beneficial effect of intermittent fasting on vascular health parameters, microcirculation, and vasodilatation has been reported. Observed effects included reduced blood pressure, increased insulin sensitivity, reduced oxidative stress, and increased levels of NO release. However, the mechanisms involved in these processes have yet to be elucidated. eGCX might consequently receive positive effects from time-restricted dietary regimes; however, repeated, and uniform studies of intermittent fasting with reliable measurement of eGCX thickness are needed to verify this hypothesis. If confirmed, time-limited dietary interventions might be a useful nutritional therapy for the vascular consequences of AD. Recent findings in this field suggest that setting the food window early in the day may be optimal due to the natural circadian rhythms of humans that control the release of hormones, thus influencing stress levels and insulin resistance.

In conclusion, more studies are being conducted to develop approaches to preserve eGCX health. As abovementioned, significant progress supported by relevant data has been achieved, however, only in experimental pharmacological treatments (Machin et al., 2023; Balistreri et al., 2024). Therefore, further studies are needed to validate the effect of such therapies in humans and confirm the possible diagnostic and prognostic role of SDCs in NDs.

This article was supported by grants from the Next Generation EU - MUR D.M. 737/2021 - Project PSEBPEHRD - CUP B79J21038330001 (to CRB).

Additional file: Open peer review reports 1 ^{(91.8KB, pdf)} and 2 ^{(91KB, pdf)} .