Genetic factors in cerebral small vessel disease and their impact on stroke and dementia

Abstract

Cerebral small vessel disease (SVD) is among the most frequent causes of both stroke and dementia. There is a growing list of genes known to be implicated in Mendelian forms of SVD. Also, genome-wide association studies have identified common variants at a number of genetic loci that are associated with manifestations of SVD, among them loci for white matter hyperintensities, small vessel stroke, and deep intracerebral hemorrhage. Driven by these discoveries and new animal models substantial progress has been made in elucidating the molecular, cellular, and physiologic mechanisms underlying SVD. A major theme emerging from these studies is the extracellular matrix (ECM). Recent findings include a role of structural constituents of the ECM such as type IV collagens in hereditary and sporadic SVD, the sequestration of proteins with a known role in ECM maintenance into aggregates of NOTCH3, and altered signaling through molecules known to interact with the ECM. Here, we review recent progress in the identification of genes involved in SVD and discuss mechanistic concepts with a particular focus on the ECM.

Figure 1.

Genetic loci implicated in cerebral small vessel disease (SVD). Circus plot of genes and genetic loci associated with SVD. Red symbols mark genes implicated in Mendelian forms of stroke. Green symbols mark genetic loci shown to be associated with one or multiple manifestations of SVD. Loci awaiting confirmation in additional samples are shown in light gray.

Figure 2.

Role of the extracellular matrix in cerebral SVD. (A) The extracellular matrix (ECM) constitutes an integral part of the vasculature. In large arteries and arterioles, the ECM is a spacious structure in which vascular smooth muscle cells are embedded, whereas in capillaries, it is restricted to the basement membrane (BM), a thin protein matrix separating the endothelium from pericytes, astrocytes, and neurons, which together form the neurovascular unit. (B) The ECM takes center stage in multiple forms of familial SVD. Left panel: COL4A1 and A2 form trimers (α1α1α2). Upon secretion, trimers assemble into a chicken-wire meshwork constituting the major structural component of BMs. Mutations in COL4A1/A2 result in impaired assembly and potentially cytotoxic accumulation of mutant heterotrimers within cells. Alternative mechanisms include the presence of mutant heterotrimers or a deficiency of properly folded heterotrimers in the BM. Both mechanisms could alter interactions with cell surface receptors and signaling molecules such integrins and BMPs; Middle panel: CADASIL-mutated NOTCH3 is efficiently secreted and participates in cell signaling. Instead of undergoing clearance from the extracellular space, the extracellular domain of mutant NOTCH3 multimerizes leading to the formation of large aggregates. Matrix proteins such as tissue inhibitor of metalloproteinases-3 (TIMP3), vitronectin (VTN), and latent TGF-β binding protein-1 (LTBP-1) are recruited into the deposits possibly resulting in an alteration of their physiologic function; Right panel: proposed model by which CARASIL mutations interfere with TGF-β signaling. Upon secretion, latent TGF-β is incorporated into the ECM via interactions of LTBP-1 with matrix proteins such as fibronectin. Mature TGF-β can be liberated from the ECM through cleavage of LTBP-1 by proteases such as HtrA1. CARASIL mutations result in a loss of HtrA1 activity and hence interfere with TGF-β signaling. BMP, bone morphogenic protein; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CARASIL, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; SVD, small vessel disease.