Transcriptional and Functional Changes of the Human Microvasculature during Physiological Aging and Alzheimer Disease

Abstract

Aging of the circulatory system correlates with the pathogenesis of a large spectrum of diseases. However, it is largely unknown which factors drive the age‐dependent or pathological decline of the vasculature and how vascular defects relate to tissue aging. The goal of the study is to design a multianalytical approach to identify how the cellular microenvironment (i.e., fibroblasts) and serum from healthy donors of different ages or Alzheimer disease (AD) patients can modulate the functionality of organ‐specific vascular endothelial cells (VECs). Long‐living human microvascular networks embedding VECs and fibroblasts from skin biopsies are generated. RNA‐seq, secretome analyses, and microfluidic assays demonstrate that fibroblasts from young donors restore the functionality of aged endothelial cells, an effect also achieved by serum from young donors. New biomarkers of vascular aging are validated in human biopsies and it is shown that young serum induces angiopoietin‐like‐4, which can restore compromised vascular barriers. This strategy is then employed to characterize transcriptional/functional changes induced on the blood–brain barrier by AD serum, demonstrating the importance of PTP4A3 in the regulation of permeability. Features of vascular degeneration during aging and AD are recapitulated, and a tool to identify novel biomarkers that can be exploited to develop future therapeutics modulating vascular function is established.

Beyond Static Pipes: Mechanisms and In Vitro Models of Vascular Aging

“…Scale bars, 50 μm. (Panel C from Bersini et al 2020a; reprinted, with permission, from the authors © 2020.) (D) Transcriptional and functional analysis of smooth muscle cells directly reprogrammed from HGPS and healthy, age-matched dermal fibroblasts donors revealed that potential markers involved in vascular permeability (i.e., bone morphogenetic protein 4 [BMP-4] and jagged 1 [JAG1]) were upregulated in HGPS-derived cells.…”

“…Interestingly, it was further demonstrated that treating these rejuvenated cells with blood serum obtained from old human donors was sufficient to reinduce signatures of vascular aging. This approach allowed the identification of potential novel vascular aging biomarkers that were validated using human tissue biopsies from donors of different ages (Bersini et al 2020a). Using a similar approach combined with the direct reprogramming of dermal fibroblasts from donors of different ages into VECs and smooth muscle cells, the same group analyzed vascular aging in the context of HGPS.…”

Advances in microfluidic in vitro systems for neurological disease modeling

“…This system also showed increased BBB permeability, decreased expression of TJPs, and increased reactive oxygen species, thus recapitulating several key aspects of BBB dysfunction observed in Alzheimer's disease patients (Shin et al., 2019). Others have used MPS to demonstrate that Alzheimer's patients’ serum can result in vascular dysfunction (Bersini et al, 2020) and to gain insights into cerebral amyloid angiopathy and vascular Aβ transport (Robert et al., 2017).…”

Therapeutic Opportunities and Delivery Strategies for Brain Revascularization in Stroke, Neurodegeneration, and Aging

“…The role of microvasculature damage/dysfunction in AD is increasingly widespread (Bersini et al, 2020;Liesz, 2019;Zlokovic, 2005). The deposition of Ab in the cerebrovasculature causes a decline in cerebral perfusion and promotes ischemic damage, accompanied by vascular and neuronal degeneration and subsequent cognitive decline (Di Marco et al, 2015;Roth et al, 2005).…”

“…Aging constitutes the main risk factor for most neurodegenerative diseases, increasing their prevalence with increasing age (Hou et al, 2019). This fact could be directly or indirectly associated with the endothelial dysfunction (Bersini et al, 2020;Ungvari et al, 2013;Ungvari et al, 2020), decline in cerebral blood flow, around 20% flow reduction, (Leenders et al, 1990;Zou et al, 2009) and BBB leakage (Verheggen et al, 2020) that occurs with aging. Additionally, scientific consensus exists on the critical role of microvasculature contributions to cognitive impairment in elderly patients (Tarantini et al, 2017).…”