Cerebral amyloid angiopathy (CAA) may result from focal to widespread amyloid-β protein (Aβ) deposition within leptomeningeal and intracortical cerebral blood vessels. In addition, pericapillary Aβ refers to Aβ depositions in the glia limitans and adjacent neuropil, whereas in capillary CAA Aβ depositions are present in the capillary wall. CAA may cause lobar intracerebral haemorrhages and microbleeds. Hypoperfusion and reduced vascular autoregulation due to CAA might cause infarcts and white matter lesions. CAA thus causes vascular lesions that potentially lead to (vascular) dementia and may further contribute to dementia by impeding the clearance of solutes out of the brain and transport of nutrients across the blood brain barrier. Severe CAA is an independent risk factor for cognitive decline. The clinical diagnosis of CAA is based on the assessment of associated cerebrovascular lesions. In addition, perivascular spaces in the white matter and reduced concentrations of both Aβ(40) and Aβ(42) in cerebrospinal fluid may prove to be suggestive for CAA. Transgenic mouse models that overexpress human Aβ precursor protein show parenchymal Aβ and CAA, thus corroborating the current concept of CAA pathogenesis: neuronal Aβ enters the perivascular drainage pathway and may accumulate in vessel walls due to increased amounts and/or decreased clearance of Aβ, respectively. We suggest that pericapillary Aβ represents early impairment of the perivascular drainage pathway while capillary CAA is associated with decreased transendothelial clearance of Aβ. CAA plays an important role in the multimorbid condition of the ageing brain but its contribution to neurodegeneration remains to be elucidated.

Amyloid β-peptide (Aβ) deposition in cerebral vessels contributes to cerebral amyloid angiopathy (CAA) in Alzheimer’s disease (AD). Here, we report that in AD patients and two mouse models of AD, overexpression of serum response factor (SRF) and myocardin (MYOCD) in cerebral vascular smooth muscle cells (VSMCs) generates an Aβ non-clearing VSMC phenotype through transactivation of sterol regulatory element binding protein-2, which downregulates low density lipoprotein receptor-related protein-1, a key Aβ clearance receptor. Hypoxia stimulated SRF/MYOCD expression in human cerebral VSMCs and in animal models of AD. We suggest that SRF and MYOCD function as a transcriptional switch, controlling Aβ cerebrovascular clearance and progression of AD.

Cerebral angiopathy contributes to cognitive decline and dementia in Alzheimer's disease (AD) through cerebral blood flow (CBF) reductions and dysregulation. We report vascular smooth muscle cells (VSMC) in small pial and intracerebral arteries, which are critical for CBF regulation, express in AD high levels of serum response factor (SRF) and myocardin (MYOCD), two interacting transcription factors that orchestrate a VSMC-differentiated phenotype. Consistent with this finding, AD VSMC overexpressed several SRF-MYOCD-regulated contractile proteins and exhibited a hypercontractile phenotype. MYOCD overexpression in control human cerebral VSMC induced an AD-like hypercontractile phenotype and diminished both endothelial-dependent and -independent relaxation in the mouse aorta ex vivo. In contrast, silencing SRF normalized contractile protein content and reversed a hypercontractile phenotype in AD VSMC. MYOCD in vivo gene transfer to mouse pial arteries increased contractile protein content and diminished CBF responses produced by brain activation in wild-type mice and in two AD models, the Dutch/Iowa/Swedish triple mutant human amyloid beta-peptide (Abeta)-precursor protein (APP)- expressing mice and APPsw(+/-) mice. Silencing Srf had the opposite effect. Expression of SRF did not change in VSMC subjected to Alzheimer's neurotoxin, Abeta. Thus, SRF-MYOCD overexpression in small cerebral arteries appears to initiate independently of Abeta a pathogenic pathway mediating arterial hypercontractility and CBF dysregulation, which are associated with Alzheimer's dementia.

ABCA1, a cholesterol transporter expressed in the brain, has been shown recently to be required to maintain normal apoE levels and lipidation in the central nervous system. In addition, ABCA1 has been reported to modulate ␤-amyloid (A␤) production in vitro. These observations raise the possibility that ABCA1 may play a role in the pathogenesis of Alzheimer disease. Here we report that the deficiency of ABCA1 does not affect soluble or guanidine-extractable A␤ levels in Tg-SwDI/B or amyloid precursor protein/presenilin 1 (APP/PS1) mice, but rather is associated with a dramatic reduction in soluble apoE levels in brain. Although this reduction in apoE was expected to reduce the amyloid burden in vivo, we observed that the parenchymal and vascular amyloid load was increased in Tg-SwDI/B animals and was not diminished in APP/ PS1 mice. Furthermore, we observed an increase in the proportion of apoE retained in the insoluble fraction, particularly in the APP/ PS1 model. These data suggested that ABCA1-mediated effects on apoE levels and lipidation influenced amyloidogenesis in vivo.Alzheimer disease (AD) 8 is the most common cause of senile dementia and currently affects ϳ40% of the population over 80 years of age. Clinically, AD is characterized by severe impairments in memory and executive cortical functions as well as difficulties in language, calculation, visuospatial perception, behavior, and judgment (1). Characteristic neuropathological hallmarks of AD include intraneuronal fibrillary tangles composed of hyperphosphorylated tau protein and amyloid deposits that are composed largely of A␤ peptides, apolipoprotein E (apoE), lipids, and other proteins that accumulate in the neural parenchyma and the cerebrovasculature (2, 3). A␤ peptides are a heterogeneous group of peptides 39 -43 amino acids in length that are proteolytically cleaved from amyloid precursor protein (APP) by ␥-and ␤-secretases (4, 5). A␤40 and A␤42 are the main A␤ species in the brain. A␤42 is less soluble and is present in all types of senile plaques, whereas A␤40 is the major species deposited in cerebral blood vessels (4 -7).Most affected individuals have late onset AD that typically manifests after 70 years of age. However, a number of families develop the disease in their 4th or 5th decades (8, 9). The cases of familial AD result from mutations within APP or secretase components (8, 10). For example, the Swedish mutation (K670M/N671L) increases the amount of A␤ peptide that is generated from APP (11, 12). Other APP mutations, including the Dutch (E693D) and Iowa (Q694N) mutations, alter the charge of the A␤ peptide and result in amyloid deposition predominantly in the cerebral blood vessels rather than in the parenchyma (13-16). In addition to mutations in APP, over 100 different mutations have been identified in presenilin-1 alone (17). However, less than 5% of the overall clinical burden of AD is caused by mutations in APP and presenilins combined.To date, the only well established risk factor for late-onset AD is apoE (18,19). In the hum...

The glymphatic system (GS) hypothesis states that advective driven cerebrospinal fluid (CSF) influx from the perivascular spaces into the interstitial fluid space rapidly transport solutes and clear waste from brain. However, the presence of advection in neuropil is contested and solutes are claimed to be transported by diffusion only. To address this controversy, we implemented a regularized version of the optimal mass transport (rOMT) problem, wherein the advection/diffusion equation is the only a priori assumption required. rOMT analysis with a Lagrangian perspective of GS transport revealed that solute speed was faster in CSF compared to grey and white matter. Further, rOMT analysis also demonstrated 2-fold differences in regional solute speed within the brain. Collectively, these results imply that advective transport dominates in CSF while diffusion and advection both contribute to GS transport in parenchyma. In a rat model of cerebral small vessel disease (cSVD), solute transport in the perivascular spaces (PVS) and PVS-to-tissue transfer was slower compared to normal rats. Thus, the analytical framework of rOMT provides novel insights in the local dynamics of GS transport that may have implications for neurodegenerative diseases. Future studies should apply the rOMT analysis approach to confirm GS transport reductions in humans with cSVD. The glymphatic system is described as a perivascular transit passageway for cerebrospinal fluid (CSF) for exchange with interstitial fluid (ISF), thereby facilitating waste drainage from the brain 1,2. Investigations of glymphatic system (GS) function have escalated given its important role in Aβ 1 and tau 3 clearance from brain and the inferred implication for neurodegeneration, including Alzheimer's disease 2,4-7. The GS is made up by the perivascular spaces (PVS), which connect with ISF via the aquaporin 4 (AQP4) water channels on astrocytic end-feet and through the small gaps between the overlapping astrocytic end-foot processes 1. The GS hypothesis states that advective CSF influx from the PVS rapidly drives interstitial solutes and waste products out via peri-venous channels 1,8. Although solute transport in the PVS along pial arteries on the surface of the brain is advective (bulk flow) and driven by cardiac pulsatility 1,9-11 , the presence of advective streams in parenchyma 12-14 is contested with the argument that advection does not occur in the neuropil and solutes are transported by diffusion only 15-21. No