Vascular senescence and leak are features of the early breakdown of the blood–brain barrier in Alzheimer’s disease models

Abstract

Alzheimer’s disease (AD) is an age-related disease, with loss of integrity of the blood–brain barrier (BBB) being an early feature. Cellular senescence is one of the reported nine hallmarks of aging. Here, we show for the first time the presence of senescent cells in the vasculature in AD patients and mouse models of AD. Senescent endothelial cells and pericytes are present in APP/PS1 transgenic mice but not in wild-type littermates at the time of amyloid deposition. In vitro, senescent endothelial cells display altered VE-cadherin expression and loss of cell junction formation and increased permeability. Consistent with this, senescent endothelial cells in APP/PS1 mice are present at areas of vascular leak that have decreased claudin-5 and VE-cadherin expression confirming BBB breakdown. Furthermore, single cell sequencing of endothelial cells from APP/PS1 transgenic mice confirms that adhesion molecule pathways are among the most highly altered pathways in these cells. At the pre-plaque stage, the vasculature shows significant signs of breakdown, with a general loss of VE-cadherin, leakage within the microcirculation, and obvious pericyte perturbation. Although senescent vascular cells were not directly observed at sites of vascular leak, senescent cells were close to the leak area. Thus, we would suggest in AD that there is a progressive induction of senescence in constituents of the neurovascular unit contributing to an increasing loss of vascular integrity. Targeting the vasculature early in AD, either with senolytics or with drugs that improve the integrity of the BBB may be valid therapeutic strategies.

Exploring the Influence of Gut–Brain Axis Modulation on Cognitive Health: A Comprehensive Review of Prebiotics, Probiotics, and Symbiotics

“…The development of Alzheimer's disease [69,[88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107] and the mechanisms through which the microbiome can contribute to the progression of Alzheimer's disease have been investigated . Numerous studies are also available regarding treatments with probiotics [139][140][141][142].…”

“…These circulating substances trigger an immune response, leading to sterile inflammation in tissues, enhancing the production of inflammatory factors (resulting in subclinical inflammation at the systemic level), and potentially serving as the basis for autoimmune processes [ 67 ]. It is likely that chronic low-grade sterile inflammation also plays a role in age-related alterations in the cerebral microcirculation, contributing to the pathogenesis of vascular cognitive impairment [ 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 ]. Probiotics play a crucial role in directly inhibiting inflammation threatening the nervous system and may prevent the circulation of substances that activate the immune system [ 42 ].…”

“…The development of Alzheimer’s disease [ 69 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 ] and the mechanisms through which the microbiome can contribute to the progression of Alzheimer’s disease have been investigated [ 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 ]. Numerous studies are also available regarding treatments with probiotics […”

Extracellular vesicles: the key to unlocking mechanisms of age-related vascular disease?

“…MMPs degrade several key ECM components that are important in maintaining integrity of the vessel wall, such as elastin, fibronectin, and laminin. Previous research showed that the degradation of elastin preceded VSMC loss and vascular calcification in a model of CKD [86] . Therefore, enhanced matrix degradation, induced by SASP, could contribute to vascular calcification.…”

Senescence and SASP Are Potential Therapeutic Targets for Ischemic Stroke

“…Stroke is a vascular disease and vascular senescence causes a myriad of downstream effects on the integrity of the BBB. BBB permeability is an early feature of age-related diseases, including Alzheimer’s disease, due to vascular senescence [ 74 , 84 ]. Chronic inflammation induced by SASP activation increases BBB permeability [ 85 ], reduces neurogenesis, and adversely affects cognitive performance [ 86 ].…”