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Acta Neuropathologica May 2020Pericyte loss and deficient vascular platelet-derived growth factor receptor-β (PDGFRβ) signaling are prominent features of the blood-brain barrier breakdown described...
Pericyte loss and deficient vascular platelet-derived growth factor receptor-β (PDGFRβ) signaling are prominent features of the blood-brain barrier breakdown described in Alzheimer's disease (AD) that can predict cognitive decline yet have never been studied in the retina. Recent reports using noninvasive retinal amyloid imaging, optical coherence tomography angiography, and histological examinations support the existence of vascular-structural abnormalities and vascular amyloid β-protein (Aβ) deposits in retinas of AD patients. However, the cellular and molecular mechanisms of such retinal vascular pathology were not previously explored. Here, by modifying a method of enzymatically clearing non-vascular retinal tissue and fluorescent immunolabeling of the isolated blood vessel network, we identified substantial pericyte loss together with significant Aβ deposition in retinal microvasculature and pericytes in AD. Evaluation of postmortem retinas from a cohort of 56 human donors revealed an early and progressive decrease in vascular PDGFRβ in mild cognitive impairment (MCI) and AD compared to cognitively normal controls. Retinal PDGFRβ loss significantly associated with increased retinal vascular Aβ and Aβ burden. Decreased vascular LRP-1 and early apoptosis of pericytes in AD retina were also detected. Mapping of PDGFRβ and Aβ levels in pre-defined retinal subregions indicated that certain geometrical and cellular layers are more susceptible to AD pathology. Further, correlations were identified between retinal vascular abnormalities and cerebral Aβ burden, cerebral amyloid angiopathy (CAA), and clinical status. Overall, the identification of pericyte and PDGFRβ loss accompanying increased vascular amyloidosis in Alzheimer's retina implies compromised blood-retinal barrier integrity and provides new targets for AD diagnosis and therapy.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloidosis; Blood-Brain Barrier; Brain; Cerebral Amyloid Angiopathy; Cognition; Female; Humans; Male; Pericytes; Retina
PubMed: 32043162
DOI: 10.1007/s00401-020-02134-w -
Journal of the Neurological Sciences Nov 2023Cerebral Amyloid Angiopathy (CAA) is a neurological disorder characterized by the deposition of amyloid plaques in the walls of cerebral blood vessels. This condition... (Review)
Review
Cerebral Amyloid Angiopathy (CAA) is a neurological disorder characterized by the deposition of amyloid plaques in the walls of cerebral blood vessels. This condition poses significant challenges in terms of understanding its underlying mechanisms, accurate diagnosis, and effective treatment strategies. This article aims to shed light on the complexities of CAA by providing insights into its pathogenesis, diagnosis, and treatment options. The pathogenesis of CAA involves the accumulation of amyloid beta (Aβ) peptides in cerebral vessels, leading to vessel damage, impaired blood flow, and subsequent cognitive decline. Various genetic and environmental factors contribute to the development and progression of CAA, and understanding these factors is crucial for targeted interventions. Accurate diagnosis of CAA often requires advanced imaging techniques, such as magnetic resonance imaging (MRI) or positron emission tomography (PET) scans, to detect characteristic amyloid deposits in the brain. Early and accurate diagnosis enables appropriate management and intervention strategies. Treatment of CAA focuses on preventing further deposition of amyloid plaques, managing associated symptoms, and reducing the risk of complications such as cerebral hemorrhage. Currently, there are no disease-modifying therapies specifically approved for CAA. However, several experimental treatments targeting Aβ clearance and anti-inflammatory approaches are being investigated in clinical trials, offering hope for future therapeutic advancements.
Topics: Humans; Amyloid beta-Peptides; Plaque, Amyloid; Cerebral Amyloid Angiopathy; Brain; Cerebral Hemorrhage; Alzheimer Disease
PubMed: 37931443
DOI: 10.1016/j.jns.2023.120866 -
Lancet (London, England) Jun 2020Alzheimer's disease and its complications are the leading cause of death in adults with Down syndrome. Studies have assessed Alzheimer's disease in individuals with Down...
BACKGROUND
Alzheimer's disease and its complications are the leading cause of death in adults with Down syndrome. Studies have assessed Alzheimer's disease in individuals with Down syndrome, but the natural history of biomarker changes in Down syndrome has not been established. We characterised the order and timing of changes in biomarkers of Alzheimer's disease in a population of adults with Down syndrome.
METHODS
We did a dual-centre cross-sectional study of adults with Down syndrome recruited through a population-based health plan in Barcelona (Spain) and through services for people with intellectual disabilities in Cambridge (UK). Cognitive impairment in participants with Down syndrome was classified with the Cambridge Cognitive Examination for Older Adults with Down Syndrome (CAMCOG-DS). Only participants with mild or moderate disability were included who had at least one of the following Alzheimer's disease measures: apolipoprotein E allele carrier status; plasma concentrations of amyloid β peptides 1-42 and 1-40 and their ratio (Aβ), total tau protein, and neurofilament light chain (NFL); tau phosphorylated at threonine 181 (p-tau), and NFL in cerebrospinal fluid (CSF); and one or more of PET with F-fluorodeoxyglucose, PET with amyloid tracers, and MRI. Cognitively healthy euploid controls aged up to 75 years who had no biomarker abnormalities were recruited from the Sant Pau Initiative on Neurodegeneration. We used a first-order locally estimated scatterplot smoothing curve to determine the order and age at onset of the biomarker changes, and the lowest ages at the divergence with 95% CIs are also reported where appropriate.
FINDINGS
Between Feb 1, 2013, and June 28, 2019 (Barcelona), and between June 1, 2009, and Dec 31, 2014 (Cambridge), we included 388 participants with Down syndrome (257 [66%] asymptomatic, 48 [12%] with prodromal Alzheimer's disease, and 83 [21%] with Alzheimer's disease dementia) and 242 euploid controls. CSF Aβ and plasma NFL values changed in individuals with Down syndrome as early as the third decade of life, and amyloid PET uptake changed in the fourth decade. F-fluorodeoxyglucose PET and CSF p-tau changes occurred later in the fourth decade of life, followed by hippocampal atrophy and changes in cognition in the fifth decade of life. Prodromal Alzheimer's disease was diagnosed at a median age of 50·2 years (IQR 47·5-54·1), and Alzheimer's disease dementia at 53·7 years (49·5-57·2). Symptomatic Alzheimer's disease prevalence increased with age in individuals with Down syndrome, reaching 90-100% in the seventh decade of life.
INTERPRETATION
Alzheimer's disease in individuals with Down syndrome has a long preclinical phase in which biomarkers follow a predictable order of changes over more than two decades. The similarities with sporadic and autosomal dominant Alzheimer's disease and the prevalence of Down syndrome make this population a suitable target for Alzheimer's disease preventive treatments.
FUNDING
Instituto de Salud Carlos III, Fundació Bancaria La Caixa, Fundació La Marató de TV3, Medical Research Council, and National Institutes of Health.
Topics: Adult; Alzheimer Disease; Amyloid beta-Peptides; Amyloidosis; Apolipoproteins E; Biomarkers; Case-Control Studies; Cognitive Dysfunction; Cross-Sectional Studies; Down Syndrome; Fluorodeoxyglucose F18; Humans; Magnetic Resonance Imaging; Middle Aged; Neurofilament Proteins; Positron-Emission Tomography; Prevalence; Spain; United Kingdom; tau Proteins
PubMed: 32593336
DOI: 10.1016/S0140-6736(20)30689-9 -
The Journal of Experimental Medicine Dec 2022TREM2 is exclusively expressed by microglia in the brain and is strongly linked to the risk for Alzheimer's disease (AD). As microglial responses modulated by TREM2 are...
TREM2 is exclusively expressed by microglia in the brain and is strongly linked to the risk for Alzheimer's disease (AD). As microglial responses modulated by TREM2 are central to AD pathogenesis, enhancing TREM2 signaling has been explored as an AD therapeutic strategy. However, the effective therapeutic window targeting TREM2 is unclear. Here, by using microglia-specific inducible mouse models overexpressing human wild-type TREM2 (TREM2-WT) or R47H risk variant (TREM2-R47H), we show that TREM2-WT expression reduces amyloid deposition and neuritic dystrophy only during the early amyloid seeding stage, whereas TREM2-R47H exacerbates amyloid burden during the middle amyloid rapid growth stage. Single-cell RNA sequencing reveals suppressed disease-associated microglia (DAM) signature and reduced DAM population upon TREM2-WT expression in the early stage, whereas upregulated antigen presentation pathway is detected with TREM2-R47H expression in the middle stage. Together, our findings highlight the dynamic effects of TREM2 in modulating AD pathogenesis and emphasize the beneficial effect of enhancing TREM2 function in the early stage of AD development.
Topics: Alzheimer Disease; Amyloid; Amyloidosis; Animals; Brain; Humans; Membrane Glycoproteins; Mice; Microglia; Receptors, Immunologic
PubMed: 36107206
DOI: 10.1084/jem.20212479 -
JACC. Cardiovascular Imaging Apr 2020This study aimed to investigate the accuracy of a broad range of echocardiographic variables to develop multiparametric scores to diagnose CA in patients with proven...
OBJECTIVES
This study aimed to investigate the accuracy of a broad range of echocardiographic variables to develop multiparametric scores to diagnose CA in patients with proven light chain (AL) amyloidosis or those with increased heart wall thickness who had amyloid was suspected. We also aimed to further characterize the structural and functional changes associated with amyloid infiltration.
BACKGROUND
Cardiac amyloidosis (CA) is a serious but increasingly treatable cause of heart failure. Diagnosis is challenging and frequently unclear at echocardiography, which remains the most often used imaging tool.
METHODS
We studied 1,187 consecutive patients evaluated at 3 referral centers for CA and analyzed morphological, functional, and strain-derived echocardiogram parameters with the aim of developing a score-based diagnostic algorithm. Cardiac amyloid burden was quantified by using extracellular volume measurements at cardiac magnetic resonance.
RESULTS
A total of 332 patients were diagnosed with AL amyloidosis and 339 patients with transthyretin CA. Concentric remodeling and strain-derived parameters displayed the best diagnostic performance. A multivariable logistic regression model incorporating relative wall thickness, E wave/e' wave ratio, longitudinal strain, and tricuspid annular plane systolic excursion had the greatest diagnostic performance in AL amyloidosis (area under the curve: 0.90; 95% confidence interval: 0.87 to 0.92), whereas the addition of septal apical-to-base ratio yielded the best diagnostic accuracy in the increased heart wall thickness group (area under the curve: 0.80; 95% confidence interval: 0.85 to 0.90).
CONCLUSIONS
Specific functional and structural parameters characterize different burdens of CA deposition with different diagnostic performances and enable the definition of 2 scores that are sensitive and specific tools with which diagnose or exclude CA.
Topics: Aged; Aged, 80 and over; Amyloid Neuropathies, Familial; Biopsy; Cardiomyopathy, Hypertrophic; Diagnosis, Differential; Echocardiography; Europe; Female; Humans; Immunoglobulin Light-chain Amyloidosis; Magnetic Resonance Imaging; Male; Middle Aged; Myocardium; Predictive Value of Tests; Ventricular Function, Left; Ventricular Remodeling
PubMed: 31864973
DOI: 10.1016/j.jcmg.2019.10.011 -
Cell Reports Aug 2019Complement pathway overactivation can lead to neuronal damage in various neurological diseases. Although Alzheimer's disease (AD) is characterized by β-amyloid plaques...
Complement pathway overactivation can lead to neuronal damage in various neurological diseases. Although Alzheimer's disease (AD) is characterized by β-amyloid plaques and tau tangles, previous work examining complement has largely focused on amyloidosis models. We find that glial cells show increased expression of classical complement components and the central component C3 in mouse models of amyloidosis (PS2APP) and more extensively tauopathy (TauP301S). Blocking complement function by deleting C3 rescues plaque-associated synapse loss in PS2APP mice and ameliorates neuron loss and brain atrophy in TauP301S mice, improving neurophysiological and behavioral measurements. In addition, C3 protein is elevated in AD patient brains, including at synapses, and levels and processing of C3 are increased in AD patient CSF and correlate with tau. These results demonstrate that complement activation contributes to neurodegeneration caused by tau pathology and suggest that blocking C3 function might be protective in AD and other tauopathies.
Topics: Alzheimer Disease; Amyloidosis; Animals; Atrophy; Behavior, Animal; Biomarkers; Brain; Complement C1q; Complement C3; Disease Models, Animal; Female; Gene Deletion; Gene Expression Regulation; Humans; Male; Mice, Transgenic; Nerve Degeneration; Neurons; Plaque, Amyloid; Synapses; Tauopathies
PubMed: 31433986
DOI: 10.1016/j.celrep.2019.07.060 -
Acta Neuropathologica Mar 2022Perivascular spaces (PVS) are compartments surrounding cerebral blood vessels that become visible on MRI when enlarged. Enlarged PVS (EPVS) are commonly seen in patients...
Perivascular spaces (PVS) are compartments surrounding cerebral blood vessels that become visible on MRI when enlarged. Enlarged PVS (EPVS) are commonly seen in patients with cerebral small vessel disease (CSVD) and have been suggested to reflect dysfunctional perivascular clearance of soluble waste products from the brain. In this study, we investigated histopathological correlates of EPVS and how they relate to vascular amyloid-β (Aβ) in cerebral amyloid angiopathy (CAA), a form of CSVD that commonly co-exists with Alzheimer's disease (AD) pathology. We used ex vivo MRI, semi-automatic segmentation and validated deep-learning-based models to quantify EPVS and associated histopathological abnormalities. Severity of MRI-visible PVS during life was significantly associated with severity of MRI-visible PVS on ex vivo MRI in formalin fixed intact hemispheres and corresponded with PVS enlargement on histopathology in the same areas. EPVS were located mainly around the white matter portion of perforating cortical arterioles and their burden was associated with CAA severity in the overlying cortex. Furthermore, we observed markedly reduced smooth muscle cells and increased vascular Aβ accumulation, extending into the WM, in individually affected vessels with an EPVS. Overall, these findings are consistent with the notion that EPVS reflect impaired outward flow along arterioles and have implications for our understanding of perivascular clearance mechanisms, which play an important role in the pathophysiology of CAA and AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Cerebral Amyloid Angiopathy; Dilatation; Glymphatic System; Humans; Magnetic Resonance Imaging
PubMed: 34928427
DOI: 10.1007/s00401-021-02393-1 -
Molecular Neurodegeneration Jun 2022Despite its identification as a key checkpoint regulator of microglial activation in Alzheimer's disease, the overarching role of CX3CR1 signaling in modulating...
BACKGROUND
Despite its identification as a key checkpoint regulator of microglial activation in Alzheimer's disease, the overarching role of CX3CR1 signaling in modulating mechanisms of Aβ driven neurodegeneration, including accumulation of hyperphosphorylated tau is not well understood.
METHODOLOGY
Accumulation of soluble and insoluble Aβ species, microglial activation, synaptic dysregulation, and neurodegeneration is investigated in 4- and 6-month old 5xFAD;Cx3cr1 and 5xFAD;Cx3cr1 mice using immunohistochemistry, western blotting, transcriptomic and quantitative real time PCR analyses of purified microglia. Flow cytometry based, in-vivo Aβ uptake assays are used for characterization of the effects of CX3CR1-signaling on microglial phagocytosis and lysosomal acidification as indicators of clearance of methoxy-X-04 fibrillar Aβ. Lastly, we use Y-maze testing to analyze the effects of Cx3cr1 deficiency on working memory.
RESULTS
Disease progression in 5xFAD;Cx3cr1 mice is characterized by increased deposition of filamentous plaques that display defective microglial plaque engagement. Microglial Aβ phagocytosis and lysosomal acidification in 5xFAD;Cx3cr1 mice is impaired in-vivo. Interestingly, Cx3cr1 deficiency results in heighted accumulation of neurotoxic, oligomeric Aβ, along with severe neuritic dystrophy, preferential loss of post-synaptic densities, exacerbated tau pathology, neuronal loss and cognitive impairment. Transcriptomic analyses using cortical RNA, coupled with qRT-PCR using purified microglia from 6 month-old mice indicate dysregulated TGFβ-signaling and heightened ROS metabolism in 5xFAD;Cx3cr1 mice. Lastly, microglia in 6 month-old 5xFAD;Cx3cr1 mice express a 'degenerative' phenotype characterized by increased levels of Ccl2, Ccl5, Il-1β, Pten and Cybb along with reduced Tnf, Il-6 and Tgfβ1 mRNA.
CONCLUSIONS
Cx3cr1 deficiency impairs microglial uptake and degradation of fibrillar Aβ, thereby triggering increased accumulation of neurotoxic Aβ species. Furthermore, loss of Cx3cr1 results in microglial dysfunction typified by dampened TGFβ-signaling, increased oxidative stress responses and dysregulated pro-inflammatory activation. Our results indicate that Aβ-driven microglial dysfunction in Cx3cr1 mice aggravates tau hyperphosphorylation, neurodegeneration, synaptic dysregulation and impairs working memory.
Topics: Alzheimer Disease; Amyloidogenic Proteins; Amyloidosis; Animals; CX3C Chemokine Receptor 1; Cognitive Dysfunction; Mice; Neurons; Plaque, Amyloid; Transforming Growth Factor beta
PubMed: 35764973
DOI: 10.1186/s13024-022-00545-9 -
Immunologic Research Aug 2023The kidney represents an important target of systemic inflammation. Its involvement in monogenic and multifactorial autoinflammatory diseases (AIDs) vary from peculiar... (Review)
Review
The kidney represents an important target of systemic inflammation. Its involvement in monogenic and multifactorial autoinflammatory diseases (AIDs) vary from peculiar and relatively frequent manifestations to some rare but severe features that may end up requiring transplantation. The pathogenetic background is also very heterogeneous ranging from amyloidosis to non-amyloid related damage rooted in inflammasome activation. Kidney involvement in monogenic and polygenic AIDs may present as renal amyloidosis, IgA nephropathy, and more rarely as various forms of glomerulonephritis (GN), namely segmental glomerulosclerosis, collapsing glomerulopathy, fibrillar, or membranoproliferative GN. Vascular disorders such as thrombosis or renal aneurysms and pseudoaneurysms may be encountered in patients with Behcet's disease. Patients with AIDs should be routinely assessed for renal involvement. Screening with urinalysis, serum creatinine, 24-h urinary protein, microhematuria, and imaging studies should be carried out for early diagnosis. Awareness of drug-induced nephrotoxicity, drug-drug interactions as well as addressing the issue of proper renal adjustment of drug doses deserve a special mention and should always be considered when dealing with patients affected by AIDs. Finally, we will explore the role of IL-1 inhibitors in AIDs patients with renal involvement. Targeting IL-1 may indeed have the potential to successfully manage kidney disease and improve long-term prognosis of AIDs patients.
Topics: Humans; Kidney; Glomerulonephritis, IGA; Amyloidosis; Hereditary Autoinflammatory Diseases; Interleukin-1
PubMed: 36991303
DOI: 10.1007/s12026-023-09375-3 -
Aging Oct 2019
Topics: Amyloidosis; Heart Diseases; Humans; Middle Aged
PubMed: 31631062
DOI: 10.18632/aging.102383