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.     

Cerebral Amyloid Angiopathy,Subcortical White Matter Disease and Dementia: Literature Review and Study in OPTIMA

Cerebral amyloid angiopathy (CAA) is of increasing clinical and research interest as the ability to detect it and its consequences by neuroimaging in living subjects has advanced. There is also increasing interest in understanding its possible role in the development of intracerebral hemorrhage, Alzheimer's disease (AD) and vascular dementia. In this article, the literature on this subject is reviewed and novel findings relating CAA to subcortical white matter damage in 224 subjects in the Oxford project to Investigate Memory and Ageing (OPTIMA) are reported. The relationship between CAA and subcortical tissue damage in the OPTIMA subjects was found to be critically dependent on ApoE genotype, there being a positive relationship between measures of CAA and subcortical small vessel disease in ApoEε4 carriers and a significant negative relationship in ApoEε2 carriers. These findings draw attention, as have many other studies, to the importance of ApoE genotype as a major risk factor not only for dementia but also for damage to blood vessels in the aging brain.     

Clusterin levels are increased in Alzheimer's disease and influence the regional distribution of Aβ

Clusterin, also known as apoJ, is a lipoprotein abundantly expressed within the CNS. It regulates Aβ fibril formation and toxicity and facilitates amyloid‐β (Aβ) transport across the blood‐brain barrier. Genome‐wide association studies have shown variations in the clusterin gene (CLU) to influence the risk of developing sporadic Alzheimer''s disease (AD). To explore whether clusterin modulates the regional deposition of Aβ, we measured levels of soluble (NP40‐extracted) and insoluble (guanidine‐HCl‐extracted) clusterin, Aβ40 and Aβ42 by sandwich ELISA in brain regions with a predilection for amyloid pathology—mid‐frontal cortex (MF), cingulate cortex (CC), parahippocampal cortex (PH), and regions with little or no pathology—thalamus (TH) and white matter (WM). Clusterin level was highest in regions with plaque pathology (MF, CC, PH and PC), approximately mirroring the regional distribution of Aβ. It was significantly higher in AD than controls, and correlated positively with Aβ42 and insoluble Aβ40. Soluble clusterin level rose significantly with severity of cerebral amyloid angiopathy, and in MF and PC regions was highest in APOE ɛ4 homozygotes. In the TH and WM (areas with little amyloid pathology) clusterin was unaltered in AD and did not correlate with Aβ level. There was a significant positive correlation between the concentration of clusterin and the regional levels of insoluble Aβ42; however, the molar ratio of clusterin : Aβ42 declined with insoluble Aβ42 level in a region‐dependent manner, being lowest in regions with predilection for Aβ plaque pathology. Under physiological conditions, clusterin reduces aggregation and promotes clearance of Aβ. Our findings indicate that in AD, clusterin increases, particularly in regions with most abundant Aβ, but because the increase does not match the rising level of Aβ42, the molar ratio of clusterin : Aβ42 in those regions falls, probably contributing to Aβ deposition within the tissue.     

White Matter Hypoperfusion and Damage in Dementia: Post‐Mortem Assessment

Neuroimaging has revealed a range of white matter abnormalities that are common in dementia, some that predict cognitive decline. The abnormalities may result from structural diseases of the cerebral vasculature, such as arteriolosclerosis and amyloid angiopathy, but can also be caused by nonstructural vascular abnormalities (eg, of vascular contractility or permeability), neurovascular instability or extracranial cardiac or vascular disease. Conventional histopathological assessment of the white matter has tended to conflate morphological vascular abnormalities with changes that reflect altered interstitial fluid dynamics or white matter ischemic damage, even though the latter may be of extracranial or nonstructural etiology. However, histopathology is being supplemented by biochemical approaches, including the measurement of proteins involved in the molecular responses to brain ischemia, myelin proteins differentially susceptible to ischemic damage, vessel‐associated proteins that allow rapid measurement of microvessel density, markers of blood–brain barrier dysfunction and axonal injury, and mediators of white matter damage. By combining neuroimaging with histopathology and biochemical analysis, we can provide reproducible, quantitative data on the severity of white matter damage, and information on its etiology and pathogenesis. Together these have the potential to inform and improve treatment, particularly in forms of dementia to which white matter hypoperfusion makes a significant contribution.     

Cerebrovascular miRNAs correlate with the clearance of Aβ through perivascular route in younger 3xTg‐AD mice

The “two‐hit vascular hypothesis for Alzheimer's disease (AD)” and amyloid‐β (Aβ) oligomer hypothesis suggest that impaired soluble Aβ oligomers clearance through the cerebral vasculature may be an initial step of the AD process. Soluble Aβ oligomers are driven into perivascular spaces from the brain parenchyma and toward peripheral blood flow. The underlying vascular‐based mechanism, however, has not been defined. Given that microRNAs (miRNAs), emerging as novel modulators, are involved in numerous physiological and pathological processes, we hypothesized that cerebrovascular miRNAs may regulate the activities of brain blood vessels, which further affects the concentration of Aβ in the AD brain. In this study, perivascular Aβ deposits, higher vascular activation, increased pericyte coverage and up‐regulated capillaries miRNAs at 6 months old (6 mo) were found to correlate with the lower Aβ levels of middle AD stage (9 mo) in 3xTg‐AD (3xTg) mice. It is implicated that at the early stage of AD when intracellular Aβ appeared, higher expression of vessel‐specific miRNAs, elevated pericyte coverage, and activated endothelium facilitate Aβ oligomer clearance through the perivascular route, resulting in a transient reduction of Aβ oligomers at 9 mo. Additionally, ghrelin‐induced upregulation of capillary miRNAs and increased pericyte coverage attenuated Aβ burden at 9 mo, in further support of the relationship between vascular miRNAs and Aβ clearance. This work suggests a cerebral microvessel miRNA may boost endothelial highly activated phenotypes to promote elimination of Aβ oligomers through the perivascular drainage pathway and contribute to AD progression. The targeting of brain vessel‐specific miRNAs may provide a new rationale for the development of innovative therapeutic strategies for AD treatment.     

From Soluble Aβ to Progressive Aβ Aggregation: Could Prion‐Like Templated Misfolding Play a Role?

Accumulation, aggregation and deposition of Aβ peptides are pathological hallmarks in the brains of individuals affected by Alzheimer's disease (AD) or by cerebral β‐amyloid angiopathy (Aβ‐CAA). While Aβ is a peptide of yet largely unknown function, it is constantly produced in the human brain where it normally remains in a soluble state. However, Aβ peptides are aggregation prone by their intrinsic ability to adopt alternative conformations rich in β‐sheet structure that aggregate into oligomeric as well as fibrillar formations. This transition from soluble to aggregated state has been hypothesized to initiate the pathological cascade and is therefore subject to intensive research. Mounting evidence suggests prion‐like templated misfolding as the biochemical phenomenon responsible for promoting progressive Aβ aggregation. Here, we review studies in vitro and in vivo that suggest that cerebral Aβ aggregation may indeed progress via prion‐like templated misfolding. The implications of these findings are discussed with respect to understanding initiation and progression of the disease and to developing therapeutics.     

Rapid amyloid‐β oligomer and protofibril accumulation in traumatic brain injury

Deposition of amyloid‐β (Aβ) is central to Alzheimer's disease (AD) pathogenesis and associated with progressive neurodegeneration in traumatic brain injury (TBI). We analyzed predisposing factors for Aβ deposition including monomeric Aβ40, Aβ42 and Aβ oligomers/protofibrils, Aβ species with pronounced neurotoxic properties, following human TBI. Highly selective ELISAs were used to analyze N‐terminally intact and truncated Aβ40 and Aβ42, as well as Aβ oligomers/protofibrils, in human brain tissue, surgically resected from severe TBI patients (n = 12; mean age 49.5 ± 19 years) due to life‐threatening brain swelling/hemorrhage within one week post‐injury. The TBI tissues were compared to post‐mortem AD brains (n = 5), to post‐mortem tissue of neurologically intact (NI) subjects (n = 4) and to cortical biopsies obtained at surgery for idiopathic normal pressure hydrocephalus patients (iNPH; n = 4). The levels of Aβ40 and Aβ42 were not elevated by TBI. The levels of Aβ oligomers/protofibrils in TBI were similar to those in the significantly older AD patients and increased compared to NI and iNPH controls (P < 0.05). Moreover, TBI patients carrying the AD risk genotype Apolipoprotein E epsilon3/4 (APOE ε3/4; n = 4) had increased levels of Aβ oligomers/protofibrils (P < 0.05) and of both N‐terminally intact and truncated Aβ42 (P < 0.05) compared to APOE ε3/4‐negative TBI patients (n = 8). Neuropathological analysis showed insoluble Aβ aggregates (commonly referred to as Aβ plaques) in three TBI patients, all of whom were APOE ε3/4 carriers. We conclude that soluble intermediary Aβ aggregates form rapidly after TBI, especially among APOE ε3/4 carriers. Further research is needed to determine whether these aggregates aggravate the clinical short‐ and long‐term outcome in TBI.     

Oligomeric Aβ in Alzheimer's Disease: Relationship to Plaque and Tangle Pathology,APOE Genotype and Cerebral Amyloid Angiopathy

Despite accumulating evidence of a central role for oligomeric amyloid β (Aβ) in the pathogenesis of Alzheimer''s Disease (AD), there is scant information on the relationship between the levels and distribution of oligomeric Aβ and those of other neurodegenerative abnormalities in AD. In the present study, we have found oligomeric Aβ to be associated with both diffuse and neuritic plaques (mostly co‐localized with Aβ_1–42) and with cerebrovascular deposits of Aβ in paraffin sections of formalin‐fixed human brain tissue. The amount of oligomeric Aβ that was labeled in the sections correlated with total Aβ plaque load, but not phospho‐tau load, cerebral amyloid angiopathy (CAA) severity or APOE genotype. Although soluble, oligomeric and insoluble Aβ levels were all significantly increased in AD brain homogenates, case‐to‐case variation and overlap between AD and controls were considerable. Over the age‐range studied (43–98 years), the levels of soluble Aβ, oligomeric Aβ₄₂, oligomeric Aβ₄₀ and insoluble Aβ did not vary significantly with age. Oligomeric Aβ_1–42 and insoluble Aβ levels were significantly higher in women. Overall, the level of insoluble Aβ, but neither oligomeric nor soluble Aβ, was associated with Braak stage, CAA severity and APOEε4 frequency, raising questions as to the role of soluble and oligomeric Aβ in the progression of AD.     

Understanding Aspects of Aluminum Exposure in Alzheimer's Disease Development

Aluminum is a ubiquitously abundant nonessential element. Aluminum has been associated with neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis, and dialysis encephalopathy. Many continue to regard aluminum as controversial although increasing evidence supports the implications of aluminum in the pathogenesis of AD. Aluminum causes the accumulation of tau protein and Aβ protein in the brain of experimental animals. Aluminum induces neuronal apoptosis in vivo and in vitro, either by endoplasmic stress from the unfolded protein response, by mitochondrial dysfunction, or a combination of them. Some, people who are exposed chronically to aluminum, either from through water and/or food, have not shown any AD pathology, apparently because their gastrointestinal barrier is more effective. This article is written keeping in mind mechanisms of action of aluminum neurotoxicity with respect to AD.     

Concurrent cardiac transthyretin and brain β amyloid accumulation among the older adults: The Hisayama study

Previous studies have revealed risk for cognitive impairment in cardiovascular diseases. We investigated the relationship between degenerative changes of the brain and heart, with reference to Alzheimer's disease (AD) pathologies, cardiac transthyretin amyloid (ATTR) deposition, and cardiac fibrosis. A total of 240 consecutive autopsy cases of a Japanese population-based study were examined. β amyloid (Aβ) of senile plaques, phosphorylated tau protein of neurofibrillary tangles, and ATTR in the hearts were immunohistochemically detected and graded according to the NIH-AA guideline for AD pathology and as Tanskanen reported, respectively. Cerebral amyloid angiopathy (CAA) was graded according to the Vonsattel scale. Cardiac fibrosis was detected by picrosirius red staining, followed by image analysis. Cardiac ATTR deposition occurred after age 75 years and increased in an age-dependent manner. ATTR deposition was more common, and of higher grades, in the dementia cases. We subdivided the cases into two age groups: ≤90 years old (n = 173) and >90 years old (n = 67), which was the mean and median age at death of the AD cases. When adjusted for age and sex, TTR deposition grades correlated with Aβ phase score (A2–3), the Consortium to Establish a Registry for AD score (sparse to frequent), and high Braak stage (V–VI) only in those aged ≤90 years at death. No significant correlation was observed between the cardiac ATTR deposition and CAA stages, or between cardiac fibrosis and AD pathologies. Collectively, AD brain pathology correlated with cardiac TTR deposition among the older adults ≤90 years.     

Pathophysiology of Hypoperfusion of the Precuneus in Early Alzheimer's Disease

The earliest decline in cerebral perfusion in Alzheimer's disease (AD) is in the medial parietal cortex (precuneus). We have analyzed precuneus in post‐mortem tissue from 70 AD and 37 control brains to explore the pathophysiology of the hypoperfusion: the contribution of arteriolosclerotic small vessel disease (SVD) and cerebral amyloid angiopathy (CAA), and of the vasoconstrictors endothelin‐1 (EDN1) and angiotensin II (Ang II), and the association with Aβ. The myelin‐associated glycoprotein:proteolipid protein‐1 ratio (MAG:PLP1) was used as an indicator of oxygenation of the precuneus prior to death. MAG:PLP1 was reduced ～50% in early AD (Braak stage III–IV). Although MAG:PLP1 remained low in advanced AD (stage V–VI), the reduction was less pronounced, possibly reflecting falling oxygen demand. Reduction in cortical MAG:PLP1 correlated with elevation in vascular endothelial growth factor (VEGF), another marker of hypoperfusion. Cortical MAG:PLP1 declined nonsignificantly with increasing SVD and CAA, but significantly with the concentration of EDN1, which was elevated approximately 75% in AD. In contrast, with reduction in cortical MAG:PLP1, Ang II level and angiotensin‐converting enzyme (ACE) activity declined, showing a normal physiological response to hypoperfusion. MAG:PLP1 was reduced in the parietal white matter (WM) in AD but here the decline correlated positively (ie, physiologically) with WM EDN1. However, the decline of MAG:PLP1 in the WM was associated with increasing cortical EDN1 and perhaps reflected vasoconstriction of perforating arterioles, which traverse the cortex to perfuse the WM. EDN1 in the cortex correlated highly significantly with both soluble and insoluble Aβ42, shown previously to upregulate neuronal endothelin‐converting enzyme‐2 (ECE2), but not with Aβ40. Our findings demonstrate reduced oxygenation of the precuneus in early AD and suggest that elevated EDN1, resulting from Aβ42‐mediated upregulation of ECE2, is a contributor.     

CD4 T cells in immunity and immunotherapy of Alzheimer's disease

Alzheimer's disease (AD) is the most common form of dementia, with prevalence progressively increasing with aging. Pathological hallmarks of the disease include accumulation of amyloid β‐protein (Aβ) peptides and neurofibrillary tangles in the brain associated with glial activation and synaptotoxicity. In addition, AD involves peripheral and brain endogenous inflammatory processes that appear to enhance disease progression. More than a decade ago a new therapeutic paradigm emerged for AD, namely the activation of the adaptive immune system directly against the self‐peptide Aβ, aimed at lowering its accumulation in the brain. This was the first time that a brain peptide was used to vaccinate human subjects in a manner similar to classic viral or bacterial vaccines. The vaccination approach has taken several forms, from initially active to passive and then back to modified active vaccines. As the first two approaches to date failed to show sufficient efficacy, the last is presently being evaluated in ongoing clinical trials. The present review summarizes the immunogenic characteristics of Aβ in humans and mice and discusses past, present and future Aβ‐based immunotherapeutic approaches for AD. We emphasize potential pathogenic and beneficial roles of CD4 T cells in light of the pathogenesis and the general decline in T‐cell responsiveness evident in the disease.     

The Recent Updates of Therapeutic Approaches Against Aβ for the Treatment of Alzheimer's Disease

One of the main neuropathological lesions observed in brain autopsy of Alzheimer's disease (AD) patients is the extracellular senile plaques mainly composed of amyloid‐beta (Aβ) peptide. Recently, treatment strategies have focused on modifying the formation, clearance, and accumulation of this potentially neurotoxic peptide. β‐ and γ‐secretase are responsible for the cleavage of amyloid precursor protein (APP) and the generation of Aβ peptide. Treatments targeting these two critical secretases may therefore reduce Aβ peptide levels and positive impact on AD. Vaccination is also an advanced approach against Aβ. This review focuses on recent advances of our understanding of this key peptide, with emphasis on Aβ peptide synthesis, accumulation and neurotoxicity, and current therapies including vaccination and two critical secretase inhibitors. MicroRNAs (miRNAs) are a class of conserved endogenous small noncoding RNAs, known to regulate the expression of complementary messenger RNAs, involved in AD development. We therefore address the relationship of miRNAs in the brain and Aβ generation, as a novel therapeutic approach to the treatment of AD while also providing new insights on the etiology of this neurological disorder. Anat Rec, 2011. © 2011 Wiley‐Liss, Inc.     

Increased Amoeboid Microglial Density in the Olfactory Bulb of Parkinson's and Alzheimer's Patients

The olfactory bulb (OB) is affected early in both Parkinson's (PD) and Alzheimer's disease (AD), evidenced by the presence of disease‐specific protein aggregates and an early loss of olfaction. Whereas previous studies showed amoeboid microglia in the classically affected brain regions of PD and AD patients, little was known about such changes in the OB. Using a morphometric approach, a significant increase in amoeboid microglia density within the anterior olfactory nucleus (AON) of AD and PD patients was observed. These amoeboid microglia cells were in close apposition to β‐amyloid, hyperphosphorylated tau or α‐synuclein deposits, but no uptake of pathological proteins by microglia could be visualized. Subsequent analysis showed (i) no correlation between microglia and α‐synuclein (PD), (ii) a positive correlation with β‐amyloid (AD), and (iii) a negative correlation with hyperphosphorylated tau (AD). Furthermore, despite the observed pathological alterations in neurite morphology, neuronal loss was not apparent in the AON of both patient groups. Thus, we hypothesize that, in contrast to the classically affected brain regions of AD and PD patients, within the AON rather than neuronal loss, the increased density in amoeboid microglial cells, possibly in combination with neurite pathology, may contribute to functional deficits.     

Aβ oligomers trigger and accelerate Aβ seeding

Aggregation of amyloid‐β (Aβ) that leads to the formation of plaques in Alzheimer's disease (AD) occurs through the stepwise formation of oligomers and fibrils. An earlier onset of aggregation is obtained upon intracerebral injection of Aβ‐containing brain homogenate into human APP transgenic mice that follows a prion‐like seeding mechanism. Immunoprecipitation of these brain extracts with anti‐Aβ oligomer antibodies or passive immunization of the recipient animals abrogated the observed seeding activity, although induced Aβ deposition was still evident. Here, we establish that, together with Aβ monomers, Aβ oligomers trigger the initial phase of Aβ seeding and that the depletion of oligomeric Aβ delays the aggregation process, leading to a transient reduction of seed‐induced Aβ deposits. This work extends the current knowledge about the role of Aβ oligomers beyond its cytotoxic nature by pointing to a role in the initiation of Aβ aggregation in vivo. We conclude that Aβ oligomers are important for the early initiation phase of the seeding process.     

Cerebral Hypoperfusion and the Energy Deficit in Alzheimer's Disease

There is a perfusion deficit in Alzheimer's disease (AD), commencing in the precuneus and spreading to other parts of the cerebral cortex. The deficit anticipates the development of dementia, contributes to brain damage, and is caused by both functional and structural abnormalities of the cerebral vasculature. Most of the abnormalities are probably secondary to the accumulation of Aβ but the consequent hypoperfusion may, in turn, increase Aβ production. In the early stages of disease, abnormalities that cause vasoconstriction predominate. These include cholinergic vascular denervation, inhibition of endothelial nitric oxide synthase, increased production of endothelin‐1 production and possibly also of angiotensin II. Patients with AD also have an increased prevalence of structural disease of cerebral microvessels, particularly CAA and capillary damage, and particularly in the later stages of disease these are likely to make an important contribution to the cerebral hypoperfusion. The metabolic abnormalities that cause early vascular dysfunction offer several targets for therapeutic intervention. However, for intervention to be effective it probably needs to be early. Prolonged cerebral hypoperfusion may induce compensatory circulatory changes that are themselves damaging, including hypertension and small vessel disease. This has implications for the use of antihypertensive drugs once there is accumulation of Aβ within the brain.     

The effect of iron in MRI and transverse relaxation of amyloid‐beta plaques in Alzheimer's disease

Dysregulation of neural iron is known to occur during the progression of Alzheimer's disease. The visualization of amyloid‐beta (Aβ) plaques with MRI has largely been credited to rapid proton relaxation in the vicinity of plaques as a result of focal iron deposition. The goal of this work was to determine the relationship between local relaxation and related focal iron content associated with Aβ plaques. Alzheimer's disease (n = 5) and control tissue (n = 3) sample slices from the entorhinal cortex were treated overnight with the iron chelator deferoxamine or saline, and microscopic gradient‐echo MRI datasets were taken. Subsequent to imaging, the same slices were stained for Aβ and iron, and then compared with regard to parametric R₂* relaxation maps and gradient‐echo‐weighted MR images. Aβ plaques in both chelated and unchelated tissue generated MR hypo‐intensities and showed relaxation rates significantly greater than the surrounding tissue. The transverse relaxation rate associated with amyloid plaques was determined not to be solely a result of iron load, as much of the relaxation associated with Aβ plaques remained following iron chelation. The data indicate a dual relaxation mechanism associated with Aβ plaques, such that iron and plaque composition synergistically produce transverse relaxation.Copyright © 2014 John Wiley & Sons, Ltd.     

Lack of variation in the nucleotide sequence corresponding to the transmembrane domain of the β-amyloid precursor protein in Alzheimer's disease

The nucleotide sequence corresponding to the APP transmembrane domain and flanking regions of charged amino acids was determined for 91 patients with histologically confirmed Alzheimer's disease, 9 patients with dementias of other etiologies, and 14 controls who had no identifiable brain disease. Twentyeight of the AD patients had a first-degree relative with dementia. No mutations were detected among the 100 demented patients. However, one of the 14 controls exhibited a change in the 3′ base of codon 716 which would not be expected to result in an amino acid substitution at this position. © 1993 Wiley-Liss, Inc.     

Tenuifolin,an extract derived from tenuigenin,inhibits amyloid‐β secretion in vitro

Aim: Previous studies have shown that tenuigenin, a crude extract of Polygala tenuifolia Willd. that is commonly used in traditional Chinese herbal medicine for memory loss, can reduce the secretion of Aβ from cultured cells. However, the mechanism underlying this effect and the active compound derived from tenuigenin is unknown. In this study, a purified component of tenuigenin, tenuifolin, was examined and revealed to be an effective compound in vitro. Methods: Aβ secretion from three sets of COS‐7 cells, each carrying a plasmid expressing a different form of APP was examined following the treatment with tenuifolin. Initially, tenuifolin was determined to have no inherent toxicity to either the transfected or wild type cells at the effective concentrations. Cells were then treated with 0.5–2.0 μg mL^?1 tenuifolin for 12 h and their media were examined via an ELISA for Aβ1‐40 and Aβ‐42. Results: We found that treatment with 2.0 μg mL^?1 tenuifolin significantly decreased Aβ secretion from COS‐7 cells without altering the ratio of Aβ1‐40 and Aβ‐42. This effect is most probably due to inhibition of the β‐site APP cleaving enzyme as Aβ secretion was not inhibited from cells expressing the C99 fragment. Conclusion: Tenuifolin is an effective compound from tenuigenin. We believe that this finding should lead the way for future experiments to determine the exact mechanism for tenuifolin’s effect on Aβ secretion.     

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.