Browsing by Subject "Cerebral amyloid angiopathy"
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Item A1 reactive astrocytes and a loss of TREM2 are associated with an early stage of pathology in a mouse model of cerebral amyloid angiopathy(BMC, 2020-07-25) Taylor, Xavier; Cisternas, Pablo; You, Yanwen; You, Yingjian; Xiang, Shunian; Marambio, Yamil; Zhang, Jie; Vidal, Ruben; Lasagna-Reeves, Cristian A.; Anatomy and Cell Biology, School of MedicineBackground Cerebral amyloid angiopathy (CAA) is typified by the cerebrovascular deposition of amyloid. The mechanisms underlying the contribution of CAA to neurodegeneration are not currently understood. Although CAA is highly associated with the accumulation of amyloid beta (Aβ), other amyloids are known to associate with the vasculature. Alzheimer’s disease (AD) is characterized by parenchymal Aβ deposition, intracellular accumulation of tau, and significant neuroinflammation. CAA increases with age and is present in 85–95% of individuals with AD. A substantial amount of research has focused on understanding the connection between parenchymal amyloid and glial activation and neuroinflammation, while associations between vascular amyloid pathology and glial reactivity remain understudied. Methods Here, we dissect the glial and immune responses associated with early-stage CAA with histological, biochemical, and gene expression analyses in a mouse model of familial Danish dementia (FDD), a neurodegenerative disease characterized by the vascular accumulation of Danish amyloid (ADan). Findings observed in this CAA mouse model were complemented with primary culture assays. Results We demonstrate that early-stage CAA is associated with dysregulation in immune response networks and lipid processing, severe astrogliosis with an A1 astrocytic phenotype, and decreased levels of TREM2 with no reactive microgliosis. Our results also indicate how cholesterol accumulation and ApoE are associated with vascular amyloid deposits at the early stages of pathology. We also demonstrate A1 astrocytic mediation of TREM2 and microglia homeostasis. Conclusion The initial glial response associated with early-stage CAA is characterized by the upregulation of A1 astrocytes without significant microglial reactivity. Gene expression analysis revealed that several AD risk factors involved in immune response and lipid processing may also play a preponderant role in CAA. This study contributes to the increasing evidence that brain cholesterol metabolism, ApoE, and TREM2 signaling are major players in the pathogenesis of AD-related dementias, including CAA. Understanding the basis for possible differential effects of glial response, ApoE, and TREM2 signaling on parenchymal plaques versus vascular amyloid deposits provides important insight for developing future therapeutic interventions.Item Amyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics(Oxford University Press, 2023) Hampel, Harald; Elhage, Aya; Cho, Min; Apostolova, Liana G.; Nicoll, James A. R.; Atri, Alireza; Neurology, School of MedicineExcess accumulation and aggregation of toxic soluble and insoluble amyloid-β species in the brain are a major hallmark of Alzheimer's disease. Randomized clinical trials show reduced brain amyloid-β deposits using monoclonal antibodies that target amyloid-β and have identified MRI signal abnormalities called amyloid-related imaging abnormalities (ARIA) as possible spontaneous or treatment-related adverse events. This review provides a comprehensive state-of-the-art conceptual review of radiological features, clinical detection and classification challenges, pathophysiology, underlying biological mechanism(s) and risk factors/predictors associated with ARIA. We summarize the existing literature and current lines of evidence with ARIA-oedema/effusion (ARIA-E) and ARIA-haemosiderosis/microhaemorrhages (ARIA-H) seen across anti-amyloid clinical trials and therapeutic development. Both forms of ARIA may occur, often early, during anti-amyloid-β monoclonal antibody treatment. Across randomized controlled trials, most ARIA cases were asymptomatic. Symptomatic ARIA-E cases often occurred at higher doses and resolved within 3-4 months or upon treatment cessation. Apolipoprotein E haplotype and treatment dosage are major risk factors for ARIA-E and ARIA-H. Presence of any microhaemorrhage on baseline MRI increases the risk of ARIA. ARIA shares many clinical, biological and pathophysiological features with Alzheimer's disease and cerebral amyloid angiopathy. There is a great need to conceptually link the evident synergistic interplay associated with such underlying conditions to allow clinicians and researchers to further understand, deliberate and investigate on the combined effects of these multiple pathophysiological processes. Moreover, this review article aims to better assist clinicians in detection (either observed via symptoms or visually on MRI), management based on appropriate use recommendations, and general preparedness and awareness when ARIA are observed as well as researchers in the fundamental understanding of the various antibodies in development and their associated risks of ARIA. To facilitate ARIA detection in clinical trials and clinical practice, we recommend the implementation of standardized MRI protocols and rigorous reporting standards. With the availability of approved amyloid-β therapies in the clinic, standardized and rigorous clinical and radiological monitoring and management protocols are required to effectively detect, monitor, and manage ARIA in real-world clinical settings.Item The Amyloid-Tau-Neuroinflammation Axis in the Context of Cerebral Amyloid Angiopathy(MDPI, 2019-12-14) Cisternas, Pablo; Taylor, Xavier; Lasagna-Reeves, Cristian A.; Anatomy and Cell Biology, School of MedicineCerebral amyloid angiopathy (CAA) is typified by the cerebrovascular deposition of amyloid. Currently, there is no clear understanding of the mechanisms underlying the contribution of CAA to neurodegeneration. Despite the fact that CAA is highly associated with the accumulation of Aβ, other types of amyloids have been shown to associate with the vasculature. Interestingly, in many cases, vascular amyloidosis has been associated with an active immune response and perivascular deposition of hyperphosphorylated tau. Despite the fact that in Alzheimer’s disease (AD) a major focus of research has been the understanding of the connection between parenchymal amyloid plaques, tau aggregates in the form of neurofibrillary tangles (NFTs), and immune activation, the contribution of tau and neuroinflammation to neurodegeneration associated with CAA remains understudied. In this review, we discussed the existing evidence regarding the amyloid diversity in CAA and its relation to tau pathology and immune response, as well as the possible contribution of molecular and cellular mechanisms, previously associated with parenchymal amyloid in AD and AD-related dementias, to the pathogenesis of CAA. The detailed understanding of the “amyloid-tau-neuroinflammation” axis in the context of CAA could open the opportunity to develop therapeutic interventions for dementias associated with CAA that are currently being proposed for AD and AD-related dementias.Item Anti-Amyloid Therapy, AD, and ARIA: Untangling the Role of CAA(MDPI, 2023-10-27) Sin, Mo-Kyung; Zamrini, Edward; Ahmed, Ali; Nho, Kwangsik; Hajjar, Ihab; Radiology and Imaging Sciences, School of MedicineAnti-amyloid therapies (AATs), such as anti-amyloid monoclonal antibodies, are emerging treatments for people with early Alzheimer’s disease (AD). AATs target amyloid β plaques in the brain. Amyloid-related imaging abnormalities (ARIA), abnormal signals seen on magnetic resonance imaging (MRI) of the brain in patients with AD, may occur spontaneously but occur more frequently as side effects of AATs. Cerebral amyloid angiopathy (CAA) is a major risk factor for ARIA. Amyloid β plays a key role in the pathogenesis of AD and of CAA. Amyloid β accumulation in the brain parenchyma as plaques is a pathological hallmark of AD, whereas amyloid β accumulation in cerebral vessels leads to CAA. A better understanding of the pathophysiology of ARIA is necessary for early detection of those at highest risk. This could lead to improved risk stratification and the ultimate reduction of symptomatic ARIA. Histopathological confirmation of CAA by brain biopsy or autopsy is the gold standard but is not clinically feasible. MRI is an available in vivo tool for detecting CAA. Cerebrospinal fluid amyloid β level testing and amyloid PET imaging are available but do not offer specificity for CAA vs amyloid plaques in AD. Thus, developing and testing biomarkers as reliable and sensitive screening tools for the presence and severity of CAA is a priority to minimize ARIA complications.Item Cerebral Amyloid Angiopathy and Downstream Alzheimer Disease Plasma Biomarkers(American Medical Association, 2025-05-01) Kang, Sung Hoon; Lee, Eun Hye; Kim, Young Ju; Jang, Hyemin; Shin, Daeun; Zetterberg, Henrik; Blennow, Kaj; Gonzalez-Ortiz, Fernando; Ashton, Nicholas J.; Yun, Jihwan; Kim, Hee Jin; Na, Duk L.; Kim, Jun Pyo; Seo, Sang Won; Radiology and Imaging Sciences, School of MedicineImportance: As amyloid-targeted therapies have become commercially available, the monitoring of cerebral amyloid angiopathy (CAA), which is an important risk factor for amyloid-related imaging abnormalities, has received increasing attention. However, comprehensive evidence on the association between Alzheimer disease (AD) plasma biomarkers and various CAA imaging markers is still lacking. Objective: To examine the association of CAA imaging markers with downstream AD plasma biomarkers in relation to amyloid-β (Aβ) uptake on positron emission tomography (PET) and whether their interplay is associated with cognitive changes. Design, setting, and participants: This registry-based cohort study in 25 hospitals across South Korea recruited participants aged 45 years or older who were registered between January 1, 2016, and December 31, 2023. Participants were categorized as having no cognitive impairment, mild cognitive impairment, or dementia of the Alzheimer type. Exposures: Cerebral amyloid angiopathy imaging markers assessed by magnetic resonance imaging, including cerebral microbleeds (CMBs), cortical superficial siderosis, white matter hyperintensities, lacunes, and enlarged perivascular spaces. Main outcomes and measures: Plasma phosphorylated tau-217 (p-tau217) was measured using a commercial assay. Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were measured using a single-molecule assay on a single platform. All participants underwent amyloid PET imaging. Associations of CAA and vascular imaging markers with downstream AD plasma biomarkers were investigated using linear regression. Results: A total of 1708 participants were included (mean [SD] age, 71.2 [8.4] years; 1044 female [61.1%]). The mean (SD) follow-up period was 4.3 (3.1) years. Lobar CMB counts and the presence of CAA were associated with downstream AD plasma biomarkers, including p-tau217 (β = 0.12 [95% CI, 0.05-0.18] and 0.29 [95% CI, 0.12-0.47], respectively), GFAP (β = 0.07 [95% CI, 0.03-0.12] and 0.20 [95% CI, 0.09-0.31], respectively), and NfL (β = 0.07 [95% CI, 0.03-0.11] and 0.16 [95% CI, 0.06-0.25], respectively) with and without the mediation of Aβ uptake on PET (indirect effect: lobar CMBs-p-tau217, 59.8% [β = 0.07 (95% CI, 0.03-0.11)]; lobar CMBs-GFAP, 49.3% [β = 0.04 (95% CI, 0.01-0.06)]; lobar CMBs-NfL, 20.9% [β = 0.01 (95% CI, 0.01-0.03)]; CAA-p-tau217, 50.9% [β = 0.15 (95% CI, 0.06-0.24)]; CAA-GFAP, 39.2% [β = 0.08 (95% CI, 0.03-0.13)]; CAA-NfL, 19.2% [β = 0.03 (95% CI, 0.01-0.05)]). Amyloid-β uptake fully mediated the associations between cortical superficial siderosis and downstream AD plasma markers. In contrast, hypertensive arteriosclerotic vascular imaging markers, including lacunes, deep CMBs, and enlarged perivascular spaces in basal ganglia, were associated with only NfL levels (β = 0.07 [95% CI, 0.01-0.13], 0.20 [95% CI, 0.08-0.32], and 0.14 [95% CI, 0.06-0.23], respectively), regardless of Aβ uptake on PET. Finally, there were interactive associations of lobar CMBs in conjunction with p-tau217 levels (β = -0.56 [95% CI, -0.79 to -0.34]) and GFAP levels (β = -0.44 [95% CI, -0.70 to -0.17]) with annual Mini-Mental State Examination changes. Conclusions and relevance: In this cohort study of participants with no cognitive impairment, mild cognitive impairment, or dementia of the Alzheimer type, a novel association was found among CAA imaging markers, downstream AD plasma biomarkers, and cognitive declines in relation to brain Aβ burdens. The findings emphasize the importance of understanding the clinical effects of amyloid-related imaging abnormality-like CAA imaging markers in light of upcoming amyloid-targeted therapies.Item Cryo-EM structures of Aβ40 filaments from the leptomeninges of individuals with Alzheimer’s disease and cerebral amyloid angiopathy(Springer Nature, 2023-12-04) Yang, Yang; Murzin, Alexey G.; Peak-Chew, Sew; Franco, Catarina; Garringer, Holly J.; Newell, Kathy L.; Ghetti, Bernardino; Goedert, Michel; Scheres, Sjors H. W.; Pathology and Laboratory Medicine, School of MedicineWe used electron cryo-microscopy (cryo-EM) to determine the structures of Aβ40 filaments from the leptomeninges of individuals with Alzheimer's disease and cerebral amyloid angiopathy. In agreement with previously reported structures, which were solved to a resolution of 4.4 Å, we found three types of filaments. However, our new structures, solved to a resolution of 2.4 Å, revealed differences in the sequence assignment that redefine the fold of Aβ40 peptides and their interactions. Filaments are made of pairs of protofilaments, the ordered core of which comprises D1-G38. The different filament types comprise one, two or three protofilament pairs. In each pair, residues H14-G37 of both protofilaments adopt an extended conformation and pack against each other in an anti-parallel fashion, held together by hydrophobic interactions and hydrogen bonds between main chains and side chains. Residues D1-H13 fold back on the adjacent parts of their own chains through both polar and non-polar interactions. There are also several additional densities of unknown identity. Sarkosyl extraction and aqueous extraction gave the same structures. By cryo-EM, parenchymal deposits of Aβ42 and blood vessel deposits of Aβ40 have distinct structures, supporting the view that Alzheimer's disease and cerebral amyloid angiopathy are different Aβ proteinopathies.Item Lead Acetate Exposure and Cerebral Amyloid Accumulation: Mechanistic Evaluations in APP/PS1 Mice(EHP, 2024) Gu, Huiying; Liu, Luqing L.; Wu, Alanna; Yu, Yongqi; Emir, Uzay; Sawiak, Stephen J.; Territo, Paul R.; Farlow, Matin R.; Zheng, Wei; Du, Yansheng; Neurology, School of MedicineBackground: The role of environmental factors in Alzheimer’s disease (AD) pathogenesis remains elusive. Mounting evidence suggests that acute and past exposure to the environmental toxicant lead (Pb) is associated with longitudinal decline in cognitive function, brain atrophy, and greater brain β-amyloid (Aβ) deposition. However, the nature of Pb-induced amyloid deposition and how it contributes to AD development remain unclear. Objectives: This study investigates the role of Pb in the pathogenesis of cerebral amyloid angiopathy (CAA) and whether plasminogen activator inhibitor-1 (PAI-1) contributes to this process in the APP/PS1 mouse model. Methods: Female APP/PS1 mice at 8 wk of age were administered either 50mg/kg Pb-acetate (PbAc) (i.e., 27mg Pb/kg) or an equivalent molar concentration of sodium acetate (NaAc) via oral gavage once daily for 8 wk. Amyloid deposition and vascular amyloid were determined by immunostaining. In addition, Aβ perivascular drainage, vascular binding assay, and microglial endocytosis were examined to determine underlying mechanisms. Furthermore, magnetic resonance imaging demyelination imaging was performed in vivo measure the level of demyelination. Finally, Y-maze and Morris water maze tests were assessed to evaluate the cognitive function of mice. Results: APP/PS1 mice (an AD mice model) exposed to PbAc demonstrated more vascular amyloid deposition less neocortical myelination, and lower cognitive function, as well as greater vascular binding to Aβ40, higher Aβ40/Aβ42 ratios, strikingly lower Aβ40 levels in the perivascular drainage, and microglial endocytosis. Importantly, exposure to a specific PAI-1 inhibitor, tiplaxtinin, which previously was reported to lower CAA pathology in mice, resulted in less CAA-related outcomes following PbAc exposure. Discussion: Our findings suggest that PbAc induced CAA/AD pathogenesis via the PAI-1 signaling in the APP/PS1 mouse model, and the inhibition of PAI-1 could be a potential therapeutic target for PbAc-mediated CAA/AD disorders.Item Plasma Biomarkers for Cerebral Amyloid Angiopathy and Implications for Amyloid-Related Imaging Abnormalities: A Comprehensive Review(MDPI, 2025-02-07) Sin, Mo-Kyung; Dage, Jeffrey L.; Nho, Kwangsik; Dowling, N. Maritza; Seyfried, Nicholas T.; Bennett, David A.; Levey, Allan I.; Ahmed, Ali; Neurology, School of MedicineAnti-amyloid therapies (AATs) are increasingly being recognized as promising treatment options for Alzheimer's disease (AD). Amyloid-related imaging abnormalities (ARIAs), small areas of edema and microbleeds in the brain presenting as abnormal signals in MRIs of the brain for patients with AD, are the most common side effects of AATs. While most ARIAs are asymptomatic, they can be associated with symptoms like nausea, headache, confusion, and gait instability and, less commonly, with more serious complications such as seizures and death. Cerebral amyloid angiopathy (CAA) has been found to be a major risk for ARIA development. The identification of sensitive and reliable non-invasive biomarkers for CAA has been an area of AD research over the years, but with the approval of AATs, this area has taken on a new urgency. This comprehensive review highlights several potential biomarkers, such as Aβ40, Aβ40/42, phosphorylated-tau217, neurofilament light chain, glial fibrillary acidic protein, secreted phosphoprotein 1, placental growth factor, triggering receptor expressed on myeloid cells 2, cluster of differentiation 163, proteomics, and microRNA. Identifying and staging CAA even before its consequences can be detected via neuroimaging are critical to allow clinicians to judiciously select appropriate candidates for AATs, stratify monitoring, properly manage therapeutic regimens for those experiencing symptomatic ARIAs, and optimize the treatment to achieve the best outcomes. Future studies can test potential plasma biomarkers in human beings and evaluate predictive values of individual markers for CAA severity.Item Tau as a mediator of neurotoxicity associated to cerebral amyloid angiopathy(BMC, 2019-02-26) You, Yingjian; Perkins, Abigail; Cisternas, Pablo; Muñoz, Braulio; Taylor, Xavier; You, Yanwen; Garringer, Holly J.; Oblak, Adrian L.; Atwood, Brady K.; Vidal, Ruben; Lasagna-Reeves, Cristian A.; Medicine, School of MedicineCerebral amyloid angiopathy (CAA) is typified by the cerebrovascular deposition of amyloid. Currently, there is no clear understanding of the mechanisms underlying the contribution of CAA to neurodegeneration. Despite the fact that CAA is highly associated with accumulation of Aβ, other types of amyloids have been shown to associate with the vasculature. Interestingly, in many cases, vascular amyloidosis is accompanied by significant tau pathology. However, the contribution of tau to neurodegeneration associated to CAA remains to be determined. We used a mouse model of Familial Danish Dementia (FDD), a neurodegenerative disease characterized by the accumulation of Danish amyloid (ADan) in the vasculature, to characterize the contribution of tau to neurodegeneration associated to CAA. We performed histological and biochemical assays to establish tau modifications associated with CAA in conjunction with cell-based and electrophysiological assays to determine the role of tau in the synaptic dysfunction associated with ADan. We demonstrated that ADan aggregates induced hyperphosphorylation and misfolding of tau. Moreover, in a mouse model for CAA, we observed tau oligomers closely associated to astrocytes in the vicinity of vascular amyloid deposits. We finally determined that the absence of tau prevents synaptic dysfunction induced by ADan oligomers. In addition to demonstrating the effect of ADan amyloid on tau misfolding, our results provide compelling evidence of the role of tau in neurodegeneration associated with ADan-CAA and suggest that decreasing tau levels could be a feasible approach for the treatment of CAA.Item Tau depletion diminishes vascular amyloid‐related deficits in a mouse model of cerebral amyloid angiopathy(Wiley, 2025) Jury-Garfe, Nur; Chimal-Juárez, Enrique; Patel, Henika; Martinez-Pinto, Jonathan; Vanderbosch, Kathryn; Mardones, Muriel D.; Perkins, Abigail; Di Prisco, Gonzalo Viana; Marambio, Yamil; Vidal, Ruben; Atwood, Brady K.; Lasagna-Reeves, Cristian A.; Anatomy, Cell Biology and Physiology, School of MedicineIntroduction: Tau is essential for amyloid beta (Aβ)-induced synaptic and cognitive deficits in Alzheimer's disease (AD), making its downregulation a therapeutic target. Cerebral amyloid angiopathy (CAA), a major vascular contributor to cognitive decline, affects over 90% of patients with AD. This study explores the impact of tau downregulation on CAA pathogenesis. Methods: We crossed the Familial Danish Dementia mouse model (Tg-FDD), which develops vascular amyloid, with tau-null (mTau-/-) mice to generate a CAA model lacking endogenous tau (Tg-FDD/mTau-/-). Behavioral, electrophysiological, histological, and transcriptomic analyses were performed. Results: Tau depletion ameliorated motor and synaptic impairments, reduced vascular amyloid deposition, and prevented vascular damage. Tau ablation also mitigated astrocytic reactivity and neuroinflammation associated with vascular amyloid accumulation. Conclusion: These findings provide the first in vivo evidence of the beneficial effects of tau downregulation in a CAA mouse model, supporting tau reduction as a potential therapeutic strategy for patients with parenchymal and vascular amyloid deposition. Highlights: Tau ablation improves motor function and synaptic impair, reduces cerebrovascular amyloid deposits, and prevents vascular damage in a mouse model of cerebral amyloid angiopathy (CAA). Tau reduction decreases astrocytic reactivity, alters neuroinflammatory gene expression, and enhances oligodendrocyte function, suggesting a protective role against neuroinflammation in CAA. These findings highlight tau reduction as a potential therapeutic strategy to mitigate CAA-induced pathogenesis, with implications for treating patients with both parenchymal and vascular amyloid deposition.