Development Of Cerebral Amyloid Angiopathy Research Articles

Age-related macular degeneration is associated with probable cerebral amyloid angiopathy: A case-control study

BackgroundAge-related macular degeneration (AMD) is a common retinal degenerative disorder among older individuals. Amyloid deposits, a hallmark of cerebral amyloid angiopathy (CAA), may be involved in the pathogenesis of AMD. Since amyloid deposits may contribute to the development of both AMD and CAA, we hypothesized that patients with AMD have a higher prevalence of CAA. ObjectiveTo compare the prevalence of CAA in patients with or without AMD matched for age. MethodsWe conducted a cross-sectional, 1:1 age-matched, case-control study of patients ≥40 years of age at the Mayo Clinic who had undergone both retinal optical coherence tomography and brain MRI from 2011 to 2015. Primary dependent variables were probable CAA, superficial siderosis, and lobar and deep cerebral microbleeds (CMBs). The relationship between AMD and CAA was assessed using multivariable logistic regression and was compared across AMD severity (none vs early vs late AMD). ResultsOur analysis included 256 age-matched pairs (AMD 126, no AMD 130). Of those with AMD, 79 (30.9%) had early AMD and 47 (19.4%) had late AMD. The mean age was 75±9 years, and there was no significant difference in vascular risk factors between groups. Patients with AMD had a higher prevalence of CAA (16.7% vs 10.0%, p=0.116) and superficial siderosis (15.1% vs 6.2%, p=0.020), but not deep CMB (5.2% vs 6.2%, p=0.426), compared to those without AMD. After adjusting for covariates, having late AMD was associated with increased odds of CAA (OR 2.83, 95% CI 1.10-7.27, p=0.031) and superficial siderosis (OR 3.40, 95%CI 1.20-9.65, p=0.022), but not deep CMB (OR 0.7, 95%CI 0.14-3.51, p=0.669). ConclusionsAMD was associated with CAA and superficial siderosis but not deep CMB, consistent with the hypothesis that amyloid deposits play a role in the development of AMD. Prospective studies are needed to determine if features of AMD may serve as biomarkers for the early diagnosis of CAA.

Emerging Roles of Endothelial Nitric Oxide in Preservation of Cognitive Health.

eNOS (endothelial nitric oxide synthase) is critically important enzyme responsible for regulation of cardiovascular homeostasis. Under physiological conditions, constitutive eNOS activity and production of endothelial nitric oxide (NO) exert essential neurovascular protective functions. In this review, we first discuss the roles of endothelial NO in prevention of neuronal amyloid accumulation and formation of neurofibrillary tangles, hallmarks of Alzheimer disease pathology. Next, we review existing evidence suggesting that NO released from endothelium prevents activation of microglia, stimulates glycolysis in astrocytes, and increases biogenesis of mitochondria. We also address major risk factors for cognitive impairment including aging and ApoE4 (apolipoprotein 4) genotype with focus on their detrimental effects on eNOS/NO signaling. Relevant to this review, recent studies suggested that aged eNOS heterozygous mice are unique model of spontaneous cerebral small vessel disease. In this regard, we review contribution of dysfunctional eNOS to deposition of Aβ (amyloid-β) into blood vessel wall leading to development of cerebral amyloid angiopathy. We conclude that endothelial dysfunction manifested by the loss of neurovascular protective functions of NO may significantly contribute to development of cognitive impairment.

Loss of cholinergic innervation differentially affects eNOS-mediated blood flow, drainage of A\u03b2 and cerebral amyloid angiopathy in the cortex and hippocampus of adult mice

Vascular dysregulation and cholinergic basal forebrain degeneration are both early pathological events in the development of Alzheimer’s disease (AD). Acetylcholine contributes to localised arterial dilatation and increased cerebral blood flow (CBF) during neurovascular coupling via activation of endothelial nitric oxide synthase (eNOS). Decreased vascular reactivity is suggested to contribute to impaired clearance of β-amyloid (Aβ) along intramural periarterial drainage (IPAD) pathways of the brain, leading to the development of cerebral amyloid angiopathy (CAA). However, the possible relationship between loss of cholinergic innervation, impaired vasoreactivity and reduced clearance of Aβ from the brain has not been previously investigated. In the present study, intracerebroventricular administration of mu-saporin resulted in significant death of cholinergic neurons and fibres in the medial septum, cortex and hippocampus of C57BL/6 mice. Arterial spin labelling MRI revealed a loss of CBF response to stimulation of eNOS by the Rho-kinase inhibitor fasudil hydrochloride in the cortex of denervated mice. By contrast, the hippocampus remained responsive to drug treatment, in association with altered eNOS expression. Fasudil hydrochloride significantly increased IPAD in the hippocampus of both control and saporin-treated mice, while increased clearance from the cortex was only observed in control animals. Administration of mu-saporin in the TetOAPPSweInd mouse model of AD was associated with a significant and selective increase in Aβ40-positive CAA. These findings support the importance of the interrelationship between cholinergic innervation and vascular function in the aetiology and/or progression of CAA and suggest that combined eNOS/cholinergic therapies may improve the efficiency of Aβ removal from the brain and reduce its deposition as CAA.

Apolipoprotein E and clusterin inhibit the early phase of amyloid-\u03b2 aggregation in an in vitro model of cerebral amyloid angiopathy

Sporadic cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid-β (Aβ) deposition, which leads to lobar hemorrhage and dementia. Biological molecules affecting the development of CAA have not been fully characterized. In this study, we performed proteome analysis of biopsied leptomeningeal and cortical vessels obtained from 6 CAA patients and 5 non-CAA patients who underwent surgery for large lobar hemorrhages. We found that 6 proteins, including Aβ, apolipoprotein E (apoE), clusterin (CLU), albumin, complement C4 and vitronectin were significantly upregulated in the vessels of CAA patients as compared to non-CAA patients. ApoE and CLU were found in all CAA patients. We next examined the effects of apoE and CLU on the early phase of Aβ aggregation, using a simple yet powerful in vitro model of CAA, which recapitulates the intramural periarterial drainage pathway model. We found that physiological concentrations of apoE and CLU delayed the initiation time of amyloid growth kinetics in a concentration-dependent manner. These data indicate that apoE and CLU may act as extracellular chaperones to inhibit Aβ amyloid deposition in CAA.

Chronic treatment with five vascular risk factors causes cerebral amyloid angiopathy but no Alzheimer pathology in C57BL6 mice

Alzheimer’s disease (AD) is a progressive neurodegenerative brain disorder and the most common form of dementia coming along with cerebral amyloid angiopathy (CAA) in more than 70% of all cases. However, CAA occurs also in pure form without AD pathology. Vascular life style risk factors such as obesity, hypertension, hypercholesterolemia, diabetes, stress or an old age play an important role in the progression of CAA. So far, no animal model for sporadic CAA has been reported, thus the aim of the present study was to create and characterize a new mouse model for sporadic CAA by treatment with different vascular risk factors. Healthy C57BL6 mice were treated with lifestyle vascular risk factors for 35 or 56 weeks: lipopolysaccharide, social stress, streptozotozin, high cholesterol diet and copper in the drinking water. Four behavioral tests (black-white box, classical maze, cheeseboard maze and plus-maze discriminative avoidance task) showed impaired learning, memory and executive functions as well as anxiety with increased age. The treated animals exhibited increased plasma levels of cortisol, insulin, interleukin-1ß, glucose and cholesterol, confirming the effectiveness of the treatment. Confocal microscopy analysis displayed severe vessel damage already after 35 weeks of treatment. IgG positive staining points to a severe blood-brain barrier (BBB) disruption and furthermore, cerebral bleedings were observed in a much higher amount in the treatment group. Importantly, inclusions of beta-amyloid in the vessels indicated the development of CAA, but no deposition of beta-amyloid plaques and tau pathology in the brains were seen. Taken together, we characterized a novel sporadic CAA mouse model, which offers a strategy to study the progression of the disease and therapeutic and diagnostic interventions.

Pericytes in Alzheimer's Disease: Novel Clues to Cerebral Amyloid Angiopathy Pathogenesis.

Pericytes in the central nervous system attract growing attention of neurobiologists because of obvious opportunities to use them as target cells in numerous brain diseases. Functional activity of pericytes includes control of integrity of the endothelial cell layer, regeneration of vascular cells, and regulation of microcirculation. Pericytes are well integrated in the so-called neurovascular unit (NVU) serving as a platform for effective communications of neurons, astrocytes, endothelial cells, and pericytes. Contribution of pericytes to the establishment and maintaining the structural and functional integrity of blood-brain barrier is confirmed in numerous experimental and clinical studies. The review covers current understandings on the role of pericytes in molecular pathogenesis of NVU/BBB dysfunction in Alzheimer's disease with the special focus on the development of cerebral amyloid angiopathy, deregulation of cerebral angiogenesis, and progression of BBB breakdown seen in Alzheimer's type neurodegeneration.

Acquired cerebral amyloid angiopathy: An emerging concept.

Cerebral amyloid angiopathy (CAA) is commonly found in older people and in patients with Alzheimer's disease (AD) accompanying cerebrovascular disorders and dementia. Early-onset CAA cases generally have been found only in rare genetic forms of CAA. Interestingly, however, CAA-related hemorrhages have been recently reported in younger people who had histories of neurosurgery with or without evidence of cadaveric dura mater grafts in childhood. It has been established in experimental settings that amyloid β-protein (Aβ) pathology can be transmitted inter-individually with Aβ seeds. Incidental Aβ pathology, predominantly Aβ-CAA, has been recognized in recipients of cadaveric dura mater grafts or cadaveric human growth hormone. These findings suggest that transmission of Aβ seeds through dura mater grafts and other contaminated materials could lead to development of CAA. In addition, neurosurgery or brain injury may contribute to cerebrovascular Aβ deposition through the disturbance of vascular Aβ drainage pathways. Thus, a novel concept, "acquired CAA," has emerged.

Patterns and severity of vascular amyloid in Alzheimer\u2019s disease associated with duplications and missense mutations in APP gene, Down syndrome and sporadic Alzheimer\u2019s disease

In this study, we have compared the severity of amyloid plaque formation and cerebral amyloid angiopathy (CAA), and the subtype pattern of CAA pathology itself, between APP genetic causes of AD (APPdup, APP mutations), older individuals with Down syndrome (DS) showing the pathology of Alzheimer’s disease (AD) and individuals with sporadic (early and late onset) AD (sEOAD and sLOAD, respectively). The aim of this was to elucidate important group differences and to provide mechanistic insights related to clinical and neuropathological phenotypes. Since lipid and cholesterol metabolism is implicated in AD as well as vascular disease, we additionally aimed to explore the role of APOE genotype in CAA severity and subtypes. Plaque formation was greater in DS and missense APP mutations than in APPdup, sEOAD and sLOAD cases. Conversely, CAA was more severe in APPdup and missense APP mutations, and in DS, compared to sEOAD and sLOAD. When stratified by CAA subtype from 1 to 4, there were no differences in plaque scores between the groups, though in patients with APPdup, APP mutations and sEOAD, types 2 and 3 CAA were more common than type 1. Conversely, in DS, sLOAD and controls, type 1 CAA was more common than types 2 and 3. APOE ε4 allele frequency was greater in sEOAD and sLOAD compared to APPdup, missense APP mutations, DS and controls, and varied between each of the CAA phenotypes with APOE ε4 homozygosity being more commonly associated with type 3 CAA than types 1 and 2 CAA in sLOAD and sEOAD. The differing patterns in CAA within individuals of each group could be a reflection of variations in the efficiency of perivascular drainage, this being less effective in types 2 and 3 CAA leading to a greater burden of CAA in parenchymal arteries and capillaries. Alternatively, as suggested by immunostaining using carboxy-terminal specific antibodies, it may relate to the relative tissue burdens of the two major forms of Aβ, with higher levels of Aβ40 promoting a more ‘aggressive’ form of CAA, and higher levels of Aβ42(3) favouring a greater plaque burden. Possession of APOE ε4 allele, especially ε4 homozygosity, favours development of CAA generally, and as type 3 particularly, in sEOAD and sLOAD.

Effects of senescence and angiotensin II on expression and processing of amyloid precursor protein in human cerebral microvascular endothelial cells.

The present study was designed to determine the effects of senescence and angiotensin II (Ang II) on expression and processing of amyloid precursor protein (APP) in human brain microvascular endothelial cells (BMECs). Senescence caused a decrease in APP expression thereby resulting in reduced secretion of soluble APPα (sAPPα). In contrast, β-site APP cleaving enzyme (BACE1) expression and production of amyloid β (Aβ)40 were increased in senescent endothelium. Importantly, in senescent human BMECs, treatment with BACE1 inhibitor IV inhibited Aβ generation and increased sAPPα production by enhancing a disintegrin and metalloprotease (ADAM)10 expression. Furthermore, Ang II impaired expression of ADAM10 and significantly reduced generation of sAPPα in senescent human BMECs. This inhibitory effect of Ang II was prevented by treatment with BACE1 inhibitor IV. Our results suggest that impairment of α-processing and shift to amyloidogenic pathway of APP contribute to endothelial dysfunction induced by senescence. Loss of sAPPα in senescent cells treated with Ang II exacerbates detrimental effects of senescence on APP processing. Notably, inhibition of BACE1 has beneficial effects on senescence induced endothelial dysfunction. Reported findings may help to explain contributions of senescent cerebral microvascular endothelium to development of cerebral amyloid angiopathy and Alzheimer’s disease (AD) pathology.

Preparation and Culturing of Human Primary Vascular Cells.

Cerebral amyloid angiopathy (CAA) results from amyloid accumulation within arteries of the cerebral cortex and leptomeninges. This condition is age-related, especially prevalent in Alzheimer's disease (AD), and the main feature of certain hereditary disorders (i.e., HCHWA-I). The vascular smooth muscle cells (VSMCs) appear to play a vital role in the development of CAA, which makes them well suited as an experimental model to study the disease and screen for possible remedies. We describe two different methods for isolating and culturing human VSMCs: First, using the human umbilical cord as an easy source of robust cells, and secondly, using brain tissue that provides the proper cerebral VSMCs, but is more problematic to work with. The umbilical cord also provides human umbilical vascular endothelial cells (HUVEC), useful primary cells for vascular research. Finally, the maintenance, preservation, and characterization of the isolated vascular cells are described.

Innate Immunity Stimulation via Toll-Like Receptor 9 Ameliorates Vascular Amyloid Pathology in Tg-SwDI Mice with Associated Cognitive Benefits

Alzheimer9s disease (AD) is characterized by the presence of parenchymal amyloid-β (Aβ) plaques, cerebral amyloid angiopathy (CAA) and neurofibrillary tangles. Currently there are no effective treatments for AD. Immunotherapeutic approaches under development are hampered by complications related to ineffectual clearance of CAA. Genome-wide association studies have demonstrated the importance of microglia in AD pathogenesis. Microglia are the primary innate immune cells of the brain. Depending on their activation state and environment, microglia can be beneficial or detrimental. In our prior work, we showed that stimulation of innate immunity with Toll-like receptor 9 agonist, class B CpG (cytosine–phosphate–guanine) oligodeoxynucleotides (ODNs), can reduce amyloid and tau pathologies without causing toxicity in Tg2576 and 3xTg-AD mouse models. However, these transgenic mice have relatively little CAA. In the current study, we evaluated the therapeutic profile of CpG ODN in a triple transgenic mouse model, Tg-SwDI, with abundant vascular amyloid, in association with low levels of parenchymal amyloid deposits. Peripheral administration of CpG ODN, both before and after the development of CAA, negated short-term memory deficits, as assessed by object-recognition tests, and was effective at improving spatial and working memory evaluated using a radial arm maze. These findings were associated with significant reductions of CAA pathology lacking adverse effects. Together, our extensive evidence suggests that this innovative immunomodulation may be a safe approach to ameliorate all hallmarks of AD pathology, supporting the potential clinical applicability of CpG ODN. <b>SIGNIFICANCE STATEMENT</b> Recent genetic studies have underscored the emerging role of microglia in Alzheimer9s disease (AD) pathogenesis. Microglia lose their amyloid-β-clearing capabilities with age and as AD progresses. Therefore, the ability to modulate microglia profiles offers a promising therapeutic avenue for reducing AD pathology. Current immunotherapeutic approaches have been limited by poor clearance of a core AD lesion, cerebral amyloid angiopathy (CAA). The present study used Tg-SwDI mice, which have extensive CAA. We found that stimulation of the innate immune system and microglia/macrophage activation via Toll-like receptor 9 using CpG (cytosine–phosphate–guanine) oligodeoxynucleotides (ODNs) leads to cognitive improvements and CAA reduction, without associated toxicity. Our data indicate that this novel concept of immunomodulation represents a safer method to reduce all aspects of AD pathology and provide essential information for potential clinical use of CpG ODN.

Neuroimaging and molecular biomarkers of dementia

Development of laboratory diagnosis and neuroimaging revealed a number of biomarkers for in vivo diagnosis of the most common forms of dementia (Alzheimer's disease, Lewy body dementia and vascular dementia). Currently, the highest diagnostic sensitivity and specificity of molecular biomarkers in the cerebrospinal fluid are detected for Alzheimer's disease. At the same time, the changes according to the magnetic resonance imaging are more prognostically significant for future cognitive decline than cerebrospinal fluid biomarkers. Cerebral microbleeds are an available adjuvant diagnostic marker, which increases the diagnostic value of leukoaraiosis that suggests the development of cerebral amyloid angiopathy or hypertensive microangiopathy, especially in cases of mixed pathology and severe cognitive deficits.

Statin Therapy and the Development of Cerebral Amyloid Angiopathy—A Rodent in Vivo Approach

Background: Cerebral amyloid angiopathy (CAA) is characterized by vascular deposition of amyloid β (Aβ) with a higher incidence of cerebral microbleeds (cMBs) and spontaneous hemorrhage. Since statins are known for their benefit in vascular disease we tested for the effect on CAA. Methods: APP23-transgenic mice received atorvastatin-supplemented food starting at the age of eight months (n = 13), 12 months (n = 7), and 16 months (n = 6), respectively. Controls (n = 16) received standard food only. At 24 months of age cMBs were determined with T2*-weighted 9.4T magnetic resonance imaging and graded by size. Results: Control mice displayed an average of 35 ± 18.5 cMBs (mean ± standard deviation), compared to 29.3 ± 9.8 in mice with eight months (p = 0.49), 24.9 ± 21.3 with 12 months (p = 0.26), and 27.8 ± 15.4 with 16 months of atorvastatin treatment (p = 0.27). In combined analysis treated mice showed lower absolute numbers (27.4 ± 15.6, p = 0.16) compared to controls and also after adjustment for cMB size (p = 0.13). Conclusion: Despite to a non-significant trend towards fewer cMBs our results failed to provide evidence for beneficial effects of long-term atorvastatin treatment in the APP23-transgenic mouse model of CAA. A higher risk for bleeding complications was not observed.

Cholesterol Potentiates &amp;lt;i&amp;gt;β&amp;lt;/i&amp;gt;-Amyloid Genesis in Cultured Human Umbilical Vein Endothelial Cells

Cerebral Amyloid Angiopathy (CAA) occurs commonly among the elderly and almost invariably in patients with Alzheimer’s Disease (AD). The β-amyloid peptides (Aβ) are produced via the amy-loidogenic processing of β-Amyloid Precursor Protein (APP) by β-secretase-1 (BACE1) and γ- secretase. Vascular endothelial cells are lately shown to possess the molecular machinery of Aβ production, which might participate in the development of CAA. Hypercholesterolemia is considered a risk factor for AD, whereas less is known if cholesterol may modulate endothelial Aβ production. In the present study we verified the amyloidogenic capability of Human Umbilical Vein Endothelial Cells (HUVECs) in vitro and explored the effect of cholesterol exposure on their amy-loidogenic potential. Cholesterol treatments at 12.5 and 25 mg/dL significantly elevated APP, BACE1 and APP β-CTF protein levels and β-site APP cleavage activity in cell lysates, and Aβ40 levels in culture medium. However, coincubation with cholesterol at 50 and 100 mg/dL attenuated the viability of the cultured cells and diminished their amyloidogenic capability. These findings suggest that high cholesterol exposure is stressful to vascular endothelial cells, and at a certain dosage range can promote an amyloidogenic response in these cells.

BACE-1 is expressed in the blood–brain barrier endothelium and is upregulated in a murine model of Alzheimer’s disease

Endothelial cells of the blood–brain barrier form a structural and functional barrier maintaining brain homeostasis via paracellular tight junctions and specific transporters such as P-glycoprotein. The blood–brain barrier is responsible for negligible bioavailability of many neuroprotective drugs. In Alzheimer’s disease, current treatment approaches include inhibitors of BACE-1 (β-site of amyloid precursor protein cleaving enzyme), a proteinase generating neurotoxic β-amyloid. It is known that BACE-1 is highly expressed in endosomes and membranes of neurons and glia. We now provide evidence that BACE-1 is expressed in blood–brain barrier endothelial cells of human, mouse, and bovine origin. We further show its predominant membrane localization by 3D-dSTORM super-resolution microscopy, and by biochemical fractionation that further shows an abluminal distribution of BACE-1 in brain microvessels. We confirm its functionality in processing APP in primary mouse brain endothelial cells. In an Alzheimer’s disease mouse model we show that BACE-1 is upregulated at the blood–brain barrier compared to healthy controls. We therefore suggest a critical role for BACE-1 at the blood–brain barrier in β-amyloid generation and in vascular aspects of Alzheimer’s disease, particularly in the development of cerebral amyloid angiopathy.

Deposition of amyloid β in the walls of human leptomeningeal arteries in relation to perivascular drainage pathways in cerebral amyloid angiopathy

Deposition of amyloid β (Aβ) in the walls of cerebral arteries as cerebral amyloid angiopathy (CAA) suggests an age-related failure of perivascular drainage of soluble Aβ from the brain. As CAA is associated with Alzheimer's disease and with intracerebral haemorrhage, the present study determines the unique sequence of changes that occur as Aβ accumulates in artery walls. Paraffin sections of post-mortem human occipital cortex were immunostained for collagen IV, fibronectin, nidogen 2, Aβ and smooth muscle actin and the immunostaining was analysed using Image J and confocal microscopy. Results showed that nidogen 2 (entactin) increases with age and decreases in CAA. Confocal microscopy revealed stages in the progression of CAA: Aβ initially deposits in basement membranes in the tunica media, replaces first the smooth muscle cells and then the connective tissue elements to leave artery walls completely or focally replaced by Aβ. The pattern of development of CAA in the human brain suggests expansion of Aβ from the basement membranes to progressively replace all tissue elements in the artery wall. Establishing this full picture of the development of CAA is pivotal in understanding the clinical presentation of CAA and for developing therapies to prevent accumulation of Aβ in artery walls. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.

Abstract W P124: Atherosclerosis Of The Circle Of Willis Is Strongly Associated With Downstream Cerebral Amyloid Angiopathy In Parenchymal Arterioles And Capillaries: Possible Mechanism For Atherosclerosis-related Intracranial Hemorrhage

Introduction: Atherosclerosis is highly associated with risk for intracranial hemorrhage. Presumed mechanisms include artery to artery embolization, arteriolar disruption by small vessel atherosclerosis, aberrant angiogenesis in poorly perfused vascular beds, and possible involvement of downstream cerebral amyloid angiopathy (CAA). Direct associations between atherosclerosis and downstream CAA have been not been supported in most studies, however these results may be confounded by the distinction between highly prevalent meningeal CAA and less frequent parenchymal CAA. Hypothesis: We hypothesized that large vessel intracranial atherosclerosis would be associated with downstream parenchymal, but not meningeal (supplied by extracranial circulation), CAA. Methods: Data were derived from the University of Kentucky brain bank (n=741). Atherosclerosis of the circle of Willis was graded on semiquantitative scale (1=0-25% occlusion; 2=25-50% occlusion; 3=50-75% occlusion; 4=75-100% occlusion). Cases were divided into those with absent (with or without meningeal CAA; n=493) and those with parenchymal CAA (n=248). Standard descriptive and comparative statistics were used for the analysis. Results: Atherosclerosis in the circle of Willis was highly associated with parenchymal (p&lt;0.001), but not meningeal CAA. Conclusions: The strong association seen between severity of atherosclerosis and parenchymal CAA suggests possible shared pathogenesis or perhaps causal development of CAA by high grade atherosclerosis. Further studies exploring this association in animal models would be helpful in clarifying this complex relationship.

Prenatal high-fat diet alters the cerebrovasculature and clearance of β-amyloid in adult offspring.

Alzheimer's disease (AD) is characterized by the accumulation of β-amyloid (Aβ) peptides in the extracellular spaces of the brain as plaques and in the walls of blood vessels as cerebral amyloid angiopathy (CAA). Failure of perivascular drainage of Aβ along cerebrovascular basement membranes contributes to the development of CAA. Mid-life hypercholesterolaemia is a risk factor for the development of AD. Maternal obesity is associated with the development of obesity, hypertension and hypercholesterolaemia in adulthood, suggesting that the risk for AD and CAA may also be influenced by the early-life environment. In the present study, we tested the hypothesis that early-life exposure to a high-fat diet results in changes to the cerebrovasculature and failure of Aβ clearance from the brain. We also assessed whether vascular Aβ deposition is greater in the brains of aged humans with a history of hyperlipidaemia, compared to age-matched controls with normal lipidaemia. Using a mouse model of maternal obesity, we found that exposure to a high-fat diet during gestation and lactation induced changes in multiple components of the neurovascular unit, including a down-regulation in collagen IV, fibronectin and apolipoprotein E, an up-regulation in markers of astrocytes and perivascular macrophages and altered blood vessel morphology in the brains of adult mice. Sustained high-fat diet over the entire lifespan resulted in additional decreases in levels of pericytes and impaired perivascular clearance of Aβ from the brain. In humans, vascular Aβ load was significantly increased in the brains of aged individuals with a history of hypercholesterolaemia. These results support a critical role for early dietary influence on the brain vasculature across the lifespan, with consequences for the development of age-related cerebrovascular and neurodegenerative diseases.

New therapeutic approaches for Alzheimer's disease and cerebral amyloid angiopathy.

Accumulating evidence has shown a strong relationship between Alzheimer’s disease (AD), cerebral amyloid angiopathy (CAA), and cerebrovascular disease. Cognitive impairment in AD patients can result from cortical microinfarcts associated with CAA, as well as the synaptic and neuronal disturbances caused by cerebral accumulations of β-amyloid (Aβ) and tau proteins. The pathophysiology of AD may lead to a toxic chain of events consisting of Aβ overproduction, impaired Aβ clearance, and brain ischemia. Insufficient removal of Aβ leads to development of CAA and plays a crucial role in sporadic AD cases, implicating promotion of Aβ clearance as an important therapeutic strategy. Aβ is mainly eliminated by three mechanisms: (1) enzymatic/glial degradation, (2) transcytotic delivery, and (3) perivascular drainage (3-“d” mechanisms). Enzymatic degradation may be facilitated by activation of Aβ-degrading enzymes such as neprilysin, angiotensin-converting enzyme, and insulin-degrading enzyme. Transcytotic delivery can be promoted by inhibition of the receptor for advanced glycation end products (RAGE), which mediates transcytotic influx of circulating Aβ into brain. Successful use of the RAGE inhibitor TTP488 in Phase II testing has led to a Phase III clinical trial for AD patients. The perivascular drainage system seems to be driven by motive force generated by cerebral arterial pulsations, suggesting that vasoactive drugs can facilitate Aβ clearance. One of the drugs promoting this system is cilostazol, a selective inhibitor of type 3 phosphodiesterase. The clearance of fluorescent soluble Aβ tracers was significantly enhanced in cilostazol-treated CAA model mice. Given that the balance between Aβ synthesis and clearance determines brain Aβ accumulation, and that Aβ is cleared by several pathways stated above, multi-drugs combination therapy could provide a mainstream cure for sporadic AD.

The Cerebrovascular Basement Membrane: Role in the Clearance of β-amyloid and Cerebral Amyloid Angiopathy.

Cerebral amyloid angiopathy (CAA), the accumulation of β-amyloid (Aβ) peptides in the walls of cerebral blood vessels, is observed in the majority of Alzheimer’s disease (AD) brains and is thought to be due to a failure of the aging brain to clear Aβ. Perivascular drainage of Aβ along cerebrovascular basement membranes (CVBMs) is one of the mechanisms by which Aβ is removed from the brain. CVBMs are specialized sheets of extracellular matrix that provide structural and functional support for cerebral blood vessels. Changes in CVBM composition and structure are observed in the aged and AD brain and may contribute to the development and progression of CAA. This review summarizes the properties of the CVBM, its role in mediating clearance of interstitial fluids and solutes from the brain, and evidence supporting a role for CVBM in the etiology of CAA.