TGFβ pathway deregulation and abnormal phospho‐SMAD2/3 staining in hereditary cerebral hemorrhage with amyloidosis‐Dutch type

Hereditary cerebral hemorrhage with amyloidosis‐Dutch type (HCHWA‐D) is an early onset hereditary form of cerebral amyloid angiopathy (CAA) pathology, caused by the E22Q mutation in the amyloid β (Aβ) peptide. Transforming growth factor β1 (TGFβ1) is a key player in vascular fibrosis and in the formation of angiopathic vessels in transgenic mice. Therefore, we investigated whether the TGFβ pathway is involved in HCHWA‐D pathogenesis in human postmortem brain tissue from frontal and occipital lobes. Components of the TGFβ pathway were analyzed with quantitative RT‐PCR. TGFβ1 and TGFβ Receptor 2 (TGFBR2) gene expression levels were significantly increased in HCHWA‐D in comparison to the controls, in both frontal and occipital lobes. TGFβ‐induced pro‐fibrotic target genes were also upregulated. We further assessed pathway activation by detecting phospho‐SMAD2/3 (pSMAD2/3), a direct TGFβ down‐stream signaling mediator, using immunohistochemistry. We found abnormal pSMAD2/3 granular deposits specifically on HCHWA‐D angiopathic frontal and occipital vessels. We graded pSMAD2/3 accumulation in angiopathic vessels and found a positive correlation with the CAA load independent of the brain area. We also observed pSMAD2/3 granules in a halo surrounding occipital vessels, which was specific for HCHWA‐D. The result of this study indicates an upregulation of TGFβ1 in HCHWA‐D, as was found previously in AD with CAA pathology. We discuss the possible origins and implications of the TGFβ pathway deregulation in the microvasculature in HCHWA‐D. These findings identify the TGFβ pathway as a potential biomarker of disease progression and a possible target of therapeutic intervention in HCHWA‐D.     

Tissue transglutaminase colocalizes with extracellular matrix proteins in cerebral amyloid angiopathy

Cerebral amyloid angiopathy (CAA) is a key histopathological hallmark of Alzheimer's disease (AD) and hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D). CAA is characterized by amyloid-beta (Aβ) depositions and remodeling of the extracellular matrix (ECM) in brain vessels and plays an important role in the development and progression of both AD and HCHWA-D. Tissue transglutaminase (tTG) modulates the ECM by molecular cross-linking of ECM proteins. Here, we investigated the distribution pattern, cellular source, and activity of tTG in CAA in control, AD, and HCHWA-D cases. We observed increased tTG immunoreactivity and colocalization with Aβ in the vessel wall in early stage CAA, whereas in later CAA stages, tTG and its cross-links were present in halos enclosing the Aβ deposition. In CAA, tTG and its cross-links at the abluminal side of the vessel were demonstrated to be either of astrocytic origin in parenchymal vessels, of fibroblastic origin in leptomeningeal vessels, and of endothelial origin at the luminal side of the deposited Aβ. Furthermore, the ECM proteins fibronectin and laminin colocalized with the tTG-positive halos surrounding the deposited Aβ in CAA. However, we observed that in situ tTG activity was present throughout the vessel wall in late stage CAA. Together, our data suggest that tTG and its activity might play a differential role in the development and progression of CAA, possibly evolving from direct modulation of Aβ aggregation to cross-linking of ECM proteins resulting in ECM restructuring.     

A Shift in Microglial β‐Amyloid Binding in Alzheimer's Disease Is Associated with Cerebral Amyloid Angiopathy

Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) are two common pathologies associated with β‐amyloid (Aβ) accumulation and inflammation in the brain; neither is well understood. The objective of this study was to evaluate human post‐mortem brains from AD subjects with purely parenchymal pathology, and those with concomitant CAA (and age‐matched controls) for differential expression of microglia‐associated Aβ ligands thought to mediate Aβ clearance and the association of these receptors with complement activation. Homogenates of brain parenchyma and enriched microvessel fractions from occipital cortex were probed for levels of C3b, membrane attack complex (MAC), CD11b and α‐2‐macroglobulin and immunoprecipitation was used to immunoprecipitate (IP) CD11b complexed with C3b and Aβ. Both C3b and MAC were significantly increased in CAA compared to AD‐only and controls and IP showed significantly increased CD11b/C3b complexes with Aβ in AD/CAA subjects. Confocal microscopy was used to visualize these interactions. MAC was remarkably associated with CAA‐affected blood vessels compared to AD‐only and control vessels. These findings are consistent with an Aβ clearance mechanism via microglial CD11b that delivers Aβ and C3b to blood vessels in AD/CAA, which leads to Aβ deposition and propagation of complement to the cytolytic MAC, possibly leading to vascular fragility.     

Cerebral amyloid angiopathy: major contributor or decorative response to Alzheimer's disease pathogenesis

Amyloid deposition within cerebral vessels, or cerebral amyloid angiopathy (CAA), is common in advanced age and even more common in Alzheimer's disease. CAA may be complicated by lobar intracerebral hemorrhage, while rare kindreds of autosomal dominant CAA also show propensity for intracerebral hemorrhage, due to germline mutations in specific amyloidogenic precursor proteins and apparent compromise of structural integrity of the blood vessel wall due to marked amyloid deposition. The relationship between cerebral amyloid angiopathy and cognitive dysfunction, however, is less clear. While cognitive dysfunction in familial CAA is likely related to prodigious amyloid deposits and vascular luminal compromise (e.g., hereditary cerebral hemorrhage with angiopathy-Dutch type (HCHWA-D)), cerebral amyloid angiopathy with intracerebral hemorrhage often presents sporadically in cognitively intact elderly patients. Moreover, while about 80% of subjects with Alzheimer's disease have demonstrable amyloid beta within blood vessel walls at autopsy, the vast majority of these fail to suffer clinically relevant intracerebral hemorrhage during life. The remaining 20% manage to progress and die of their disease with virtual no amyloid within blood vessels. Thus, the role of amyloid beta deposits in cerebral vessels as regards cognitive function on the one hand, and tendency for hemorrhage on the other, remain to be resolved for sporadic late onset Alzheimer's disease and CAA. Recent studies on transgenic APP23 mice suggest a relationship between passive immunization and amyloid angiopathy-associated cerebral hemorrhage, although the mechanism of hemorrhage was unclear from the data presented. We suggest that amyloid accumulation represents a response to chronic stress, and that the neurodegenerative process occurs at the neuronal level, encompassing oxidative stress and aberrant cell cycle activation. As such, CAA represents tissue homeostasis, such that an abrupt perturbation of this balance (e.g., amyloid beta immunization) is deleterious.     

Solubilized cystatin C amyloid is cytotoxic to cultured human cerebrovascular smooth muscle cells

Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid 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. The vascular smooth muscle cells (VSMC) appear to play a vital role in the development of CAA and have been found to produce the amyloid beta precursor protein (AbetaPP) and process it to Abeta the major component of most CAA amyloid. Moreover, synthesized Abeta has proven to be toxic to cerebral VSMC in culture possibly explaining the disintegration and disappearance of the muscle cells from affected cerebral blood vessels seen in CAA. An aggressive and extremely rare form of CAA, known as Hereditary Cerebral Hemorrhage With Amyloidosis-Icelandic Type (HCHWA-I), exhibits this withdrawal of VSMC as amyloid accumulates in the vessel wall. However, the amyloid in HCHWA-I is made from a variant of cystatin C (L68Q) instead of the more common Abeta. To evaluate possible cytotoxicity in this condition solubilized cystatin C amyloid extracted from HCHWA-I leptomeninges was applied to cerebral smooth muscle cells in culture and was found to kill the cells.     

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. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

The cerebral beta-amyloid angiopathies: hereditary and sporadic

We review the clinical, radiologic, and neuropathologic features of the hereditary and sporadic forms of cerebral amyloid angiopathy (CAA) associated with vascular deposition of the beta-amyloid peptide. Amino acid substitutions at 4 sites in the beta-amyloid precursor protein, all situated within the beta-amyloid peptide sequence itself, have been shown to cause heritable forms of CAA. The vascular diseases caused by these mutations are associated primarily with cerebral hemorrhages, white matter lesions, and cognitive impairment, and only variable extents of the plaque and neurofibrillary pathologies characteristic of Alzheimer disease. Sporadic CAA typically presents 20 or more years later than hereditary CAA, but is otherwise characterized by a comparable constellation of recurrent cerebral hemorrhages, white matter lesions, and cognitive impairment. The clinical, radiologic and pathologic similarities between hereditary and sporadic CAA suggest that important lessons for this common age-related process can be learned from the mechanisms by which mutation makes beta-amyloid tropic or toxic to vessels.     

Prominent cerebral amyloid angiopathy in transgenic mice overexpressing the london mutant of human APP in neurons

Deposition of amyloid beta-peptide (Abeta) in cerebral vessel walls (cerebral amyloid angiopathy, CAA) is very frequent in Alzheimer's disease and occurs also as a sporadic disorder. Here, we describe significant CAA in addition to amyloid plaques, in aging APP/Ld transgenic mice overexpressing the London mutant of human amyloid precursor protein (APP) exclusively in neurons. The number of amyloid-bearing vessels increased with age, from approximately 10 to >50 per coronal brain section in APP/Ld transgenic mice, aged 13 to 24 months. Vascular amyloid was preferentially deposited in arterioles and ranged from small focal to large circumferential depositions. Ultrastructural analysis allowed us to identify specific features contributing to weakening of the vessel wall and aneurysm formation, ie, disruption of the external elastic lamina, thinning of the internal elastic lamina, interruption of the smooth muscle layer, and loss of smooth muscle cells. Biochemically, the much lower Abeta42:Abeta40 ratio evident in vascular relative to plaque amyloid, demonstrated that in blood vessel walls Abeta40 was the more abundant amyloid peptide. The exclusive neuronal origin of transgenic APP, the high levels of Abeta in cerebrospinal fluid compared to plasma, and the specific neuroanatomical localization of vascular amyloid strongly suggest specific drainage pathways, rather than local production or blood uptake of Abeta as the primary mechanism underlying CAA. The demonstration in APP/Ld mice of rare vascular amyloid deposits that immunostained only for Abeta42, suggests that, similar to senile plaque formation, Abeta42 may be the first amyloid to be deposited in the vessel walls and that it entraps the more soluble Abeta40. Its ability to diffuse for larger distances along perivascular drainage pathways would also explain the abundance of Abeta40 in vascular amyloid. Consistent with this hypothesis, incorporation of mutant presenilin-1 in APP/Ld mice, which resulted in selectively higher levels of Abeta42, caused an increase in CAA and senile plaques. This mouse model will be useful in further elucidating the pathogenesis of CAA and Alzheimer's disease, and will allow testing of diagnostic and therapeutic strategies.     

Neprilysin protects against cerebral amyloid angiopathy and Aβ-induced degeneration of cerebrovascular smooth muscle cells

Neprilysin (NEP), which degrades amyloid-β (Aβ), is expressed by neurons and cerebrovascular smooth muscle cells (CVSMCs). NEP immunolabeling is reduced within cerebral blood vessels of Alzheimer's disease (AD) patients with cerebral amyloid angiopathy (CAA). We have now measured NEP enzyme activity in leptomeningeal and purified cerebral cortical blood vessel preparations from control and AD patients with and without CAA. Measurements were adjusted for smooth muscle actin (SMA) to control for variations in CVSMC content. NEP activity was reduced in CAA, in both controls and AD. In leptomeningeal vessels, NEP activity was related to APOE genotype, being highest in ε2-positive and lowest in ε4-positive brains. To assess the role of NEP in protecting CVSMCs from Aβ toxicity, we measured cell death in primary human adult CVSMCs exposed to Aβ(1-40) , Aβ(1-42) or Aβ(1-40(Dutch variant)) . Aβ(1-42) was most cytotoxic to CVSMCs. Aβ(1-42) -mediated cell death was increased following siRNA-mediated knockdown or thiorphan-mediated inhibition of NEP activity; conversely Aβ(1-42) -mediated cytotoxicity was reduced by the addition of somatostatin and NEP over-expression following transfection with NEP cDNA. Our findings suggest that NEP protects CVSMCs from Aβ toxicity and protects cerebral blood vessels from the development and complications of CAA.     

Capillary cerebral amyloid angiopathy is associated with vessel occlusion and cerebral blood flow disturbances

The role of cerebral amyloid angiopathy (CAA) in the pathogenesis of Alzheimer's disease (AD) is not fully understood. Here, we studied whether CAA is associated with alterations in microvascularisation in transgenic mouse models and in the human brain. APP23 mice at 25–26 months of age exhibited severe CAA in thalamic vessels whereas APP51/16 mice did not. Wild-type littermates were free of CAA. We found CAA-related capillary occlusion within the thalamus of APP23 mice but not in APP51/16 and wild-type mice. Magnetic resonance angiography (MRA) showed blood flow alterations in the thalamic vessels of APP23 mice. CAA-related capillary occlusion in the branches of the thalamoperforating arteries of APP23 mice, thereby, corresponded to the occurrence of blood flow disturbances. Similarly, CAA-related capillary occlusion was observed in the human occipital cortex of AD cases but less frequently in controls. These results indicate that capillary CAA can result in capillary occlusion and is associated with cerebral blood flow disturbances providing an additional mechanism for toxic effects of the amyloid β-protein in AD.     

Dexamethasone diminishes the pro-inflammatory and cytotoxic effects of amyloid β-protein in cerebrovascular smooth muscle cells

Background  

Cerebrovascular deposition of fibrillar amyloid β-protein (Aβ), a condition known as cerebral amyloid angiopathy (CAA), is a prominent pathological feature of Alzheimer's disease (AD) and related disorders. Accumulation of cerebral vascular fibrillar Aβ is implicated in promoting local neuroinflammation, causes marked degeneration of smooth muscle cells, and can lead to loss of vessel wall integrity with hemorrhage. However, the relationship between cerebral vascular fibrillar Aβ-induced inflammatory responses and localized cytotoxicity in the vessel wall remains unclear.     

Microvasculature in Brain Biopsy Specimens from Patients with Alzheimer's Disease: An Immunohistochemical and Ultrastructural Study

Brain biopsy specimens from five patients with Alzheimer's disease obtained in the course of a trial of intracerebroventricular bethanechol were studied by immunohistochemical (antibody to A₄ peptide) and ultrastructural techniques, with particular emphasis on the microvessels. In some cases, numbers of A₄-immunoreactive lesions (senile plaques) correlated well with numbers of plaques demonstrable by silver stains. Prominent A₄-immunoreactive amyloid angiopathy was seen in one patient. The patient with severe cerebral amyloid angiopathy (CAA) showed extensive arteriolar deposition of amyloid filaments with apparent destruction of the media but remarkably intact endothelium. A cell of origin for amyloid filaments was not apparent, although close proximity to smooth muscle cell remnants in the arteriolar media suggested this as one possible cell of origin. Frequent vessels showed medial or adventitial collagen deposition, even when the amount of amyloid was minimal or negligible. Thus relatively severe CAA can exist in the absence of overt endothelial injury, although related studies on this tissue indicate definite abnormalities of the blood-brain barrier. Conversely, destruction of smooth muscle cells and collagen deposition in vessel walls may be the cellular correlates of arteriolar weakening that can lead to CAA-related brain hemorrhage.     

Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis

The E693Q mutation in the amyloid beta precursor protein (APP) leads to cerebral amyloid angiopathy (CAA), with recurrent cerebral hemorrhagic strokes and dementia. In contrast to Alzheimer disease (AD), the brains of those affected by hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) show few parenchymal amyloid plaques. We found that neuronal overexpression of human E693Q APP in mice (APPDutch mice) caused extensive CAA, smooth muscle cell degeneration, hemorrhages and neuroinflammation. In contrast, overexpression of human wild-type APP (APPwt mice) resulted in predominantly parenchymal amyloidosis, similar to that seen in AD. In APPDutch mice and HCHWA-D human brain, the ratio of the amyloid-beta40 peptide (Abeta40) to Abeta42 was significantly higher than that seen in APPwt mice or AD human brain. Genetically shifting the ratio of AbetaDutch40/AbetaDutch42 toward AbetaDutch42 by crossing APPDutch mice with transgenic mice producing mutated presenilin-1 redistributed the amyloid pathology from the vasculature to the parenchyma. The understanding that different Abeta species can drive amyloid pathology in different cerebral compartments has implications for current anti-amyloid therapeutic strategies. This HCHWA-D mouse model is the first to develop robust CAA in the absence of parenchymal amyloid, highlighting the key role of neuronally produced Abeta to vascular amyloid pathology and emphasizing the differing roles of Abeta40 and Abeta42 in vascular and parenchymal amyloid pathology.     

Subcortical vascular dementia

Subcortical vascular dementia (SVD) is a small vessel disease with dementia that exhibits relatively uniform clinical and pathological features and constitutes approximately half of vascular dementia (VaD) cases. This subtype is further classified into Binswanger's disease and multiple lacunar infarctions. The former is characterized by diffuse white matter lesions, and the latter is characterized by lacunar infarctions. Both of these entities are related to hypertensive small vessel changes. Subcortical vascular dementia may exhibit slowly progressive vascular Parkinsonism and dementia but can be differentiated from Alzheimer's disease because it is associated with more extensive white matter lesions, less severe hippocampal atrophy and the absence of cerebral amyloid angiopathy (CAA), which may be indicated radiologically by lobar microbleeds, cortical subarachnoid hemorrhage (SAH) and cortical microinfarctions. Cerebral amyloid angiopathy may manifest as dementia and constitute the cortical type counterpart of SVD in small vessel disease with dementia.This paper provides an overview of the clinical features, pathogenesis and treatment for SVD, as well as its relationship to CAA and Alzheimer's disease.     

Failure of Perivascular Drainage of β‐amyloid in Cerebral Amyloid Angiopathy

In Alzheimer's disease, amyloid‐β (Aβ) accumulates as insoluble plaques in the brain and deposits in blood vessel walls as cerebral amyloid angiopathy (CAA). The severity of CAA correlates with the degree of cognitive decline in dementia. The distribution of Aβ in the walls of capillaries and arteries in CAA suggests that Aβ is deposited in the perivascular pathways by which interstitial fluid drains from the brain. Soluble Aβ from the extracellular spaces of gray matter enters the basement membranes of capillaries and drains along the arterial basement membranes that surround smooth muscle cells toward the leptomeningeal arteries. The motive force for perivascular drainage is derived from arterial pulsations combined with the valve effect of proteins present in the arterial basement membranes. Physical and biochemical changes associated with arteriosclerosis, aging and possession of apolipoprotein E4 genotype lead to a failure of perivascular drainage of soluble proteins, including Aβ. Perivascular cells associated with arteries and the lymphocytes recruited in the perivenous spaces contribute to the clearance of Aβ. The failure of perivascular clearance of Aβ may be a major factor in the accumulation of Aβ in CAA and may have significant implications for the design of therapeutics for the treatment of Alzheimer's disease.     

Neuropathology and Genetics of Cerebroretinal Vasculopathies

Cerebroretinal vasculopathy (CRV) and the related diseases hereditary endotheliopathy with retinopathy, neuropathy, and stroke (HERNS), hereditary vascular retinopathy (HVR) and hereditary systemic angiopathy (HSA) [subsequently combined as retinovasculopathy and cerebral leukodystrophy (RVCL)] are devastating autosomal‐dominant disorders of early to middle‐age onset presenting with a core constellation of neurologic and ophthalmologic findings. This family of diseases is linked by specific mutations targeting a core region of a gene. Frameshift mutations in the carboxyl‐terminus of t hree p rime e xonuclease‐1 (TREX1), the major mammalian 3′ to 5′ DNA exonuclease on chromosome 3p21.1‐p21.3, result in a systemic vasculopathy that follows an approximately 5‐year course leading to death secondary to progressive neurologic decline, with sometimes a more protracted course in HERNS. Neuropathological features include a fibrinoid vascular necrosis or thickened hyalinized vessels associated with white matter ischemia, necrosis and often striking dystrophic calcifications. Ultrastructural studies of the vessel walls often demonstrate unusual multilaminated basement membranes.     

LRP1 expression in cerebral cortex,choroid plexus and meningeal blood vessels: Relationship to cerebral amyloid angiopathy and APOE status

APOE genotype is a risk factor for Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). The risk and severity of CAA increase with possession of APOE ?4, whereas APOE ?2 increases the risk of vessel rupture. Uptake of Aβ by cerebrovascular smooth muscle cells (CVSMCs) is mediated by low-density lipoprotein receptor-related protein-1 (LRP1). To determine whether APOE influences CAA by altering LRP1 expression, particularly by CVSMCs, we analysed APOE genotype, CAA severity, and LRP1 levels in post-mortem cerebral cortex, choroid plexus and meningeal vessels. LRP1 mRNA and protein were not related to CAA severity and presence. LRP1 mRNA was increased in meningeal vessels, but not cortex or choroid plexus, in AD and in association with APOE ?4, and was decreased in association with APOE ?3. In brains with CAA, APOE ?2 was associated with decreased LRP1 protein in meningeal vessels, and ?3 with increased LRP1 in choroid plexus. These findings suggest that APOE may influence the severity of CAA through altered expression of LRP1.     

Vascular amyloid alters astrocytic water and potassium channels in mouse models and humans with Alzheimer's disease

The neurovascular unit (NVU) comprises cerebral blood vessels and surrounding astrocytes, neurons, perivascular microglia and pericytes. Astrocytes associated with the NVU are responsible for maintaining cerebral blood flow and ionic and osmotic balances in the brain. A significant proportion of individuals with Alzheimer's disease (AD) have vascular amyloid deposits (cerebral amyloid angiopathy, CAA) that contribute to the heterogeneous nature of the disease. To determine whether NVU astrocytes are affected by the accumulation of amyloid at cerebral blood vessels we examined astrocytic markers in four transgenic mouse models of amyloid deposition. These mouse models represent mild CAA, moderate CAA with disease progression to tau pathology and neuron loss, severe CAA and severe CAA with disease progression to tau pathology and neuron loss. We found that CAA and disease progression both resulted in distinct NVU astrocytic changes. CAA causes a loss of apparent glial fibrillary acidic protein (GFAP)–positive astrocytic end-feet and loss of water channels (aquaporin 4) localized to astrocytic end feet. The potassium channels Kir4.1, an inward rectifying potassium channel, and BK, a calcium-sensitive large-conductance potassium channel, were also lost. The anchoring protein, dystrophin 1, is common to these channels and was reduced in association with CAA. Disease progression was associated with a phenotypic switch in astrocytes indicated by a loss of GFAP-positive cells and a gain of S100β-positive cells. Aquaporin 4, Kir4.1 and dystrophin 1 were also reduced in autopsied brain tissue from individuals with AD that also display moderate and severe CAA. Together, these data suggest that damage to the neurovascular unit may be a factor in the pathogenesis of Alzheimer's disease.     

Acute phase proteins but not activated microglial cells are present in parenchymal β/A4 deposits in the brains of patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type

With immunohistochemical staining methods on cryostat sections we investigated the brains of three patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type, one of the cerebral β/A4 amyloid diseases. Immunostaining for β/A4 protein revealed numerous non-fibrillar β/A4 depositions (amorphous or diffuse plaques) in the brain parenchyma in addition to extensive vascular amyloid deposition. All amorphous plaques contain complement proteins and ₁-antichymotrypsin but activated microglial cells expressing major histocompatibility (MHC) class II antigens HLA-DR and leucocyte adhesion molecules belonging to the lymphocyte-function-associated antigen (LFA)-1 family are virtually absent in cortical gray matter. Our findings are discussed from the view that a cascade of events including acute phase proteins and activated microglial cells are involved in classical amyloid plaque formation.     

Sporadic and familial cerebral amyloid angiopathies

Cerebral amyloid angiopathy (CAA) is the term used to describe deposition of amyloid in the walls of arteries, arterioles and, less often, capillaries and veins of the central nervous system. CAAs are an important cause of cerebral hemorrhage and may also result in ischemic lesions and dementia. A number of amyloid proteins are known to cause CAA. The most common sporadic CAA, caused by A beta deposition, is associated with aging and is a common feature of Alzheimer disease (AD). CAA occurs in several familial conditions, including hereditary cerebral hemorrhage with amyloidosis of Icelandic type caused by deposition of mutant cystatin C, hereditary cerebral hemorrhage with amyloidosis Dutch type and familial AD with deposition of either A beta variants or wild-type A beta, the transthyretin-related meningo-vascular amyloidoses, gelsolin as well as familial prion disease-related CAAs and the recently described BRI2 gene-related CAAs in familial British dementia and familial Danish dementia. This review focuses on the morphological, biochemical, and genetic aspects as well as the clinical significance of CAAs with special emphasis on the BRI2 gene-related cerebrovascular amyloidoses. We also discuss data relevant to the pathomechanism of the different forms of CAA with an emphasis on the most common A beta-related types.