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Vascular cognitive impairment and dementia (VCID) is commonly caused by vascular injuries in cerebral large and small vessels and is a key driver of age-related cognitive decline. Severe VCID includes post-stroke dementia, subcortical ischemic vascular dementia, multi-infarct dementia, and mixed dementia. While VCID is acknowledged as the second most common form of dementia after Alzheimer’s disease (AD) accounting for 20% of dementia cases, VCID and AD frequently coexist. In VCID, cerebral small vessel disease (cSVD) often affects arterioles, capillaries, and venules, where arteriolosclerosis and cerebral amyloid angiopathy (CAA) are major pathologies. White matter hyperintensities, recent small subcortical infarcts, lacunes of presumed vascular origin, enlarged perivascular space, microbleeds, and brain atrophy are neuroimaging hallmarks of cSVD. The current primary approach to cSVD treatment is to control vascular risk factors such as hypertension, dyslipidemia, diabetes, and smoking. However, causal therapeutic strategies have not been established partly due to the heterogeneous pathogenesis of cSVD. In this review, we summarize the pathophysiology of cSVD and discuss the probable etiological pathways by focusing on hypoperfusion/hypoxia, blood–brain barriers (BBB) dysregulation, brain fluid drainage disturbances, and vascular inflammation to define potential diagnostic and therapeutic targets for cSVD.

Cerebral amyloid angiopathy (CAA) is characterized by accumulation of amyloid β (Aβ) in walls of leptomeningeal vessels and cortical capillaries in the brain. The loss of integrity of these vessels caused by cerebrovascular Aβ deposits results in fragile vessels and lobar intracerebral hemorrhages. CAA also manifests with progressive cognitive impairment or transient focal neurological symptoms. Although development of therapeutics for CAA is urgently needed, the pathogenesis of CAA remains to be fully elucidated. In this review, we summarize the epidemiology, pathology, clinical and radiological features, and perspectives for future research directions in CAA therapeutics. Recent advances in mass spectrometric methodology combined with vascular isolation techniques have aided understanding of the cerebrovascular proteome. In this paper, we describe several potential key CAA-associated molecules that have been identified by proteomic analyses (apolipoprotein E, clusterin, SRPX1 (sushi repeat-containing protein X-linked 1), TIMP3 (tissue inhibitor of metalloproteinases 3), and HTRA1 (HtrA serine peptidase 1)), and their pivotal roles in Aβ cytotoxicity, Aβ fibril formation, and vessel wall remodeling. Understanding the interactions between cerebrovascular Aβ deposits and molecules that accumulate with Aβ may lead to discovery of effective CAA therapeutics and to the identification of biomarkers for early diagnosis.

Microglial involvement in Alzheimer’s disease (AD) pathology has emerged as a risk-determining pathogenic event. While apolipoprotein E ( APOE ) is known to modify AD risk, it remains unclear how microglial apoE impacts brain cognition and AD pathology. Here, using conditional mouse models expressing apoE isoforms in microglia and central nervous system-associated macrophages (CAMs), we demonstrate a cell-autonomous effect of apoE3-mediated microglial activation and function, which are negated by apoE4. Expression of apoE3 in microglia/CAMs improves cognitive function, increases microglia surrounding amyloid plaque and reduces amyloid pathology and associated toxicity, whereas apoE4 expression either compromises or has no effects on these outcomes by impairing lipid metabolism. Single-cell transcriptomic profiling reveals increased antigen presentation and interferon pathways upon apoE3 expression. In contrast, apoE4 expression downregulates complement and lysosomal pathways, and promotes stress-related responses. Moreover, in the presence of mouse endogenous apoE, microglial apoE4 exacerbates amyloid pathology. Finally, we observed a reduction in Lgals3-positive responsive microglia surrounding amyloid plaque and an increased accumulation of lipid droplets in APOE4 human brains and induced pluripotent stem cell-derived microglia. Our findings establish critical isoform-dependent effects of microglia/CAM-expressed apoE in brain function and the development of amyloid pathology, providing new insight into how apoE4 vastly increases AD risk. Liu and colleagues find differential effects of microglial apoE isoforms on brain function and microglial responses. ApoE3 enhances microglial responses, promoting brain function and reducing amyloid deposition and associated neurotoxicity, while the Alzheimer’s disease-associated apoE4 results in lipid droplet accumulation and impaired microglial responses, which are critical for limiting the development of amyloid pathology.

The ε4 allele of the apolipoprotein E (APOE) gene, a genetic risk factor for Alzheimer’s disease, is abundantly expressed in both the brain and periphery. Here, we present evidence that peripheral apoE isoforms, separated from those in the brain by the blood–brain barrier, differentially impact Alzheimer’s disease pathogenesis and cognition. To evaluate the function of peripheral apoE, we developed conditional mouse models expressing human APOE3 or APOE4 in the liver with no detectable apoE in the brain. Liver-expressed apoE4 compromised synaptic plasticity and cognition by impairing cerebrovascular functions. Plasma proteome profiling revealed apoE isoform-dependent functional pathways highlighting cell adhesion, lipoprotein metabolism and complement activation. ApoE3 plasma from young mice improved cognition and reduced vessel-associated gliosis when transfused into aged mice, whereas apoE4 compromised the beneficial effects of young plasma. A human induced pluripotent stem cell-derived endothelial cell model recapitulated the plasma apoE isoform-specific effect on endothelial integrity, further supporting a vascular-related mechanism. Upon breeding with amyloid model mice, liver-expressed apoE4 exacerbated brain amyloid pathology, whereas apoE3 reduced it. Our findings demonstrate pathogenic effects of peripheral apoE4, providing a strong rationale for targeting peripheral apoE to treat Alzheimer’s disease.Mouse models expressing liver apoE in the absence of brain apoE reveal detrimental effects of peripheral apoE4 associated with Alzheimer’s risk on cognition and amyloid pathology through compromising vascular integrity and function.

To uncover molecular changes underlying blood-brain-barrier dysfunction in Alzheimer’s disease, we performed single nucleus RNA sequencing in 24 Alzheimer’s disease and control brains and focused on vascular and astrocyte clusters as main cell types of blood-brain-barrier gliovascular-unit. The majority of the vascular transcriptional changes were in pericytes. Of the vascular molecular targets predicted to interact with astrocytic ligands, SMAD3 , upregulated in Alzheimer’s disease pericytes, has the highest number of ligands including VEGFA , downregulated in Alzheimer’s disease astrocytes. We validated these findings with external datasets comprising 4,730 pericyte and 150,664 astrocyte nuclei. Blood SMAD3 levels are associated with Alzheimer’s disease-related neuroimaging outcomes. We determined inverse relationships between pericytic SMAD3 and astrocytic VEGFA in human iPSC and zebrafish models. Here, we detect vast transcriptome changes in Alzheimer’s disease at the gliovascular-unit, prioritize perturbed pericytic SMAD3 -astrocytic VEGFA interactions, and validate these in cross-species models to provide a molecular mechanism of blood-brain-barrier disintegrity in Alzheimer’s disease. Systematic studies are needed to discover molecular determinants of blood brain barrier dysfunction in Alzheimer’s disease. This study identifies perturbed pericytic SMAD3-astrocytic VEGFA interactions as a potential driver of this dysfunction.

Sporadic cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid beta (Aβ) deposits and causes cerebral hemorrhages and dementia in elderly people. Memantine is used in Alzheimer’s disease to inhibit the glutamatergic system by blocking N -methyl- d -aspartate receptors. Its therapeutic effects in CAA are unclear, however. Here, we used APP23 transgenic mice (CAA model) to investigate whether memantine has direct therapeutic effects on cerebrovascular Aβ deposits. We treated APP23 mice and age-matched wild-type littermates with memantine at ages 6–18 months. We counted the numbers of vessels with Aβ and hemosiderin deposits. We measured soluble and insoluble Aβ40 and Aβ42 levels and levels of amyloid precursor protein (APP), APP-processing enzymes (α-, β-, γ-secretase), and Aβ-degrading enzymes (insulin-degrading enzyme [IDE], neprilysin). Memantine reduced cerebrovascular Aβ and hemosiderin deposits in APP23 mice. Compared with controls, memantine-treated APP23 mice had reduced Aβ40 levels and increased levels of hippocampal and vascular IDE. Our results suggest that memantine reduces cerebrovascular Aβ deposits by enhancing Aβ-cleaving IDE expression. The clinical availability of memantine may allow its use as a novel therapeutic agent in CAA.

The maturation of brain microvascular endothelial cells leads to the formation of a tightly sealed monolayer, known as the blood–brain barrier (BBB). The BBB damage is associated with the pathogenesis of age-related neurodegenerative diseases including vascular cognitive impairment and Alzheimer’s disease. Growing knowledge in the field of epigenetics can enhance the understanding of molecular profile of the BBB and has great potential for the development of novel therapeutic strategies or targets to repair a disrupted BBB. Histone deacetylases (HDACs) inhibitors are epigenetic regulators that can induce acetylation of histones and induce open chromatin conformation, promoting gene expression by enhancing the binding of DNA with transcription factors. We investigated how HDAC inhibition influences the barrier integrity using immortalized human endothelial cells (HCMEC/D3) and the human induced pluripotent stem cell (iPSC)-derived brain vascular endothelial cells. The endothelial cells were treated with or without a novel compound named W2A-16. W2A-16 not only activates Wnt/β-catenin signaling but also functions as a class I HDAC inhibitor. We demonstrated that the administration with W2A-16 sustained barrier properties of the monolayer of endothelial cells, as evidenced by increased trans-endothelial electrical resistance (TEER). The BBB-related genes and protein expression were also increased compared with non-treated controls. Analysis of transcript profiles through RNA-sequencing in hCMEC/D3 cells indicated that W2A-16 potentially enhances BBB integrity by influencing genes associated with the regulation of the extracellular microenvironment. These findings collectively propose that the HDAC inhibition by W2A-16 plays a facilitating role in the formation of the BBB. Pharmacological approaches to inhibit HDAC may be a potential therapeutic strategy to boost and/or restore BBB integrity.

Sporadic cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid beta (Aβ) deposits and causes cerebral hemorrhage and dementia. The exact molecules that co-accumulate with cerebrovascular Aβ deposits are still not fully known. In our study here, we performed proteomic analyses with microdissected leptomeningeal arteries and cerebral neocortical arterioles from 8 cases with severe CAA, 12 cases with mild CAA, and 10 control cases without CAA, and we determined the levels of highly expressed proteins in cerebral blood vessels in CAA. We focused on sushi repeat-containing protein 1 (SRPX1), which is specifically expressed in CAA-affected cerebral blood vessels. Because SRPX1, which is known as a tumor suppressor gene, reportedly induced apoptosis in tumor cells, we hypothesized that SRPX1 may play an important role in Aβ-induced apoptosis in CAA. Immunohistochemical studies revealed that SRPX1 co-accumulated with Aβ deposits in cerebral blood vessels of all autopsied cases with severe CAA. In contrast, no SRPX1 co-accumulated with Aβ deposits in senile plaques. Furthermore, we demonstrated that both Aβ40 and Aβ42 bound to SRPX1 in vitro and enhanced SRPX1 expression in primary cultures of cerebrovascular smooth muscle cells. SRPX1 enhanced caspase activity induced by Aβ40. Knockdown of SRPX1, in contrast, reduced the formation of Aβ40 accumulations and the activity of caspase in cultured cerebrovascular smooth muscle cells. SRPX1 may thus be a novel molecule that is up-regulated in cerebrovascular Aβ deposits and that may increase Aβ-induced cerebrovascular degeneration in CAA.

Cerebral small vessel disease (cSVD) is the most common cause of vascular cognitive impairment and dementia (VCID) and highly associated with Alzheimer’s disease pathogenesis. There is an urgent need to establish relevant animal models for cSVD. As aging is the strongest risk factor for these diseases, cerebrovascular senescence is implicated in cSVD pathogenesis. We investigated how AAV-based expression of senescence marker CDKN2A/p16 INK4A in cerebrovascular endothelial cells influences cSVD phenotypes in adult wild-type mice. A single intraperitoneal injection of the AAV carrying CDKN2A/p16 INK4A caused blood-brain barrier impairments, neurovascular uncoupling, and reduction of cerebral blood flow, accompanied with behavioral changes in mice. While single cell RNA-sequencing and immunostaining revealed the upregulation of VCAM1 in cerebrovascular endothelial cells, in vivo two-photon excitation microscopy detected aggravated leukocyte adhesions to capillaries. Our findings demonstrate the contributions of p16 INK4A in cerebrovascular endothelial cells to cSVD and VCID pathogenesis through new mouse model.

Cerebrovasculature is critical in maintaining brain homeostasis; its dysregulation often leads to vascular cognitive impairment and dementia (VCID) during aging. VCID is the second most prevalent cause of dementia in the elderly, after Alzheimer's disease (AD), with frequent cooccurrence of VCID and AD. While multiple factors are involved in the pathogenesis of AD and VCID, APOE4 increases the risk for both diseases. A major apolipoprotein E (apoE) receptor, the low-density lipoprotein receptor-related protein 1 (LRP1), is abundantly expressed in vascular mural cells (pericytes and smooth muscle cells). Here, we investigated how deficiency of vascular mural cell LRP1 affects the cerebrovascular system and cognitive performance using vascular mural cell-specific Lrp1-KO mice (smLrp1-/-) in a human APOE3 or APOE4 background. We found that spatial memory was impaired in the 13- to 16-month-old APOE4 smLrp1-/- mice but not in the APOE3 smLrp1-/- mice, compared with their respective littermate control mice. These disruptions in the APOE4 smLrp1-/- mice were accompanied with excess paravascular glial activation and reduced cerebrovascular collagen IV. In addition, blood-brain barrier (BBB) integrity was disrupted in the APOE4 smLrp1-/- mice. Together, our results suggest that vascular mural cell LRP1 modulates cerebrovasculature integrity and function in an APOE genotype-dependent manner.