RESUMO
BACKGROUND: Toxoplasma gondii infection of Alzheimer's disease model mice decreases amyloid ß plaques. We aimed to determine if there is a brain regional difference in amyloid ß reduction in the brains of T. gondii-infected compared to control mice. METHOD: Three-month-old 5xFAD (AD model) mice were injected with T. gondii or with phosphate-buffered saline as a control. Intact brains were harvested at 6 weeks postinfection, optically cleared using iDISCO+, and brain-wide amyloid burden was visualized using volumetric light-sheet imaging. Amyloid signal was quantified across each brain and computationally mapped to the Allen Institute Brain Reference Atlas to determine amyloid density in each region. RESULTS: A brain-wide analysis of amyloid in control and T. gondii-infected 5xFAD mice revealed that T. gondii infection decreased amyloid burden in the brain globally as well as in the cortex and hippocampus, and many daughter regions. Daughter regions that showed reduced amyloid burden included the prelimbic cortex, visual cortex, and retrosplenial cortex. The olfactory tubercle, a region known to have increased monocytes following T. gondii infection, also showed reduced amyloid after infection. CONCLUSIONS: T. gondii infection of AD mice reduces amyloid burden in a brain region-specific manner that overlaps with known regions of T. gondii infection and peripheral immune cell infiltration.
Assuntos
Doença de Alzheimer , Encéfalo , Modelos Animais de Doenças , Camundongos Transgênicos , Toxoplasma , Animais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/parasitologia , Doença de Alzheimer/patologia , Camundongos , Encéfalo/parasitologia , Encéfalo/metabolismo , Encéfalo/patologia , Peptídeos beta-Amiloides/metabolismo , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Toxoplasmose/metabolismo , FemininoRESUMO
The brain changes of Alzheimer's disease (AD) include Abeta (Aß) amyloid plaques ("A"), abnormally phosphorylated tau tangles ("T"), and neurodegeneration ("N"). These have been used to construct in vivo and postmortem diagnostic and staging classifications for evaluating the spectrum of AD in the "ATN" and "ABC" ("B" for Braak tau stage, "C" for Consortium to Establish a Registry for Alzheimer's Disease [CERAD] neuritic plaque density) systems. Another common AD feature involves cerebral amyloid angiopathy (CAA). We report the first experiment to examine relationships among cognition, brain distribution of amyloid plaques, CAA, tau/tangles, and magnetic resonance imaging (MRI)-determined volume changes (as a measure of "N") in the same group of behaviorally characterized nonhuman primates. Both ATN and ABC systems were applied to a group of 32 rhesus macaques aged between 7 and 33 years. When an immunohistochemical method for "T" and "B" was used, some monkeys were "triple positive" on ATN, with a maximum ABC status of A1B2C3. With silver or thioflavin S methods, however, all monkeys were classified as T-negative and B0, indicating the absence of mature neurofibrillary tangles (NFTs) and hence neuropathologically defined AD. Although monkeys at extremes of the ATN and ABC classifications, or with frequent CAA, had significantly lower scores on some cognitive tests, the lack of fully mature NFTs or dementia-consistent cognitive impairment indicates that fully developed AD may not occur in rhesus macaques. There were sex differences noted in the types of histopathology present, and only CAA was significantly related to gray matter volume.
Assuntos
Envelhecimento , Doença de Alzheimer , Encéfalo , Substância Cinzenta , Macaca mulatta , Imageamento por Ressonância Magnética , Animais , Doença de Alzheimer/patologia , Doença de Alzheimer/diagnóstico por imagem , Masculino , Feminino , Imageamento por Ressonância Magnética/métodos , Envelhecimento/patologia , Envelhecimento/fisiologia , Humanos , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Placa Amiloide/patologia , Placa Amiloide/diagnóstico por imagem , Emaranhados Neurofibrilares/patologia , Cognição/fisiologia , Transtornos Cognitivos/patologia , Transtornos Cognitivos/diagnóstico por imagem , Proteínas tau/metabolismoRESUMO
Systemic amyloidosis involves the deposition of misfolded proteins in organs/tissues, leading to progressive organ dysfunction and failure. Congo red is the gold-standard chemical stain for visualizing amyloid deposits in tissue, showing birefringence under polarization microscopy. However, Congo red staining is tedious and costly to perform, and prone to false diagnoses due to variations in amyloid amount, staining quality and manual examination of tissue under a polarization microscope. We report virtual birefringence imaging and virtual Congo red staining of label-free human tissue to show that a single neural network can transform autofluorescence images of label-free tissue into brightfield and polarized microscopy images, matching their histochemically stained versions. Blind testing with quantitative metrics and pathologist evaluations on cardiac tissue showed that our virtually stained polarization and brightfield images highlight amyloid patterns in a consistent manner, mitigating challenges due to variations in chemical staining quality and manual imaging processes in the clinical workflow.
Assuntos
Amiloide , Aprendizado Profundo , Microscopia de Fluorescência , Coloração e Rotulagem , Humanos , Birrefringência , Amiloide/metabolismo , Microscopia de Fluorescência/métodos , Coloração e Rotulagem/métodos , Vermelho Congo , Microscopia de Polarização/métodos , Amiloidose/patologia , Amiloidose/metabolismo , Amiloidose/diagnóstico por imagem , Imagem Óptica/métodos , Placa Amiloide/patologia , Placa Amiloide/metabolismo , Placa Amiloide/diagnóstico por imagem , Miocárdio/patologia , Miocárdio/metabolismoRESUMO
Progressive cerebral volume loss on MRI is a hallmark of Alzheimer's disease and has been widely used as an outcome measure in clinical trials, with the prediction that disease-modifying treatments would slow loss. However, in trials of anti-amyloid immunotherapy, the participants who received treatment had excess volume loss. Explanations for this observation range from reduction of amyloid ß plaque burden and related inflammatory changes through to treatment-induced toxicity. The excess volume changes are characteristic of only those immunotherapies that achieve amyloid ß lowering; are compatible with plaque removal; and evidence to date does not suggest an association with harmful effects. Based on the current evidence, we suggest that these changes can be described as amyloid-removal-related pseudo-atrophy. Better understanding of the causes and consequences of these changes is important to enable informed decisions about treatments. Patient-level analyses of data from the trials are urgently needed, along with longitudinal follow-up and neuroimaging data, to determine the long-term trajectory of these volume changes and their clinical correlates. Post-mortem examination of cerebral tissue from treated patients and evaluation of potential correlation with antemortem neuroimaging findings are key priorities.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Atrofia , Encéfalo , Imunoterapia , Humanos , Doença de Alzheimer/terapia , Doença de Alzheimer/diagnóstico por imagem , Imunoterapia/métodos , Peptídeos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Placa Amiloide/patologia , Imageamento por Ressonância MagnéticaRESUMO
Brain-wide profiling of diverse biological components is fundamental for understanding complex brain pathology. Despite the availability in whole-brain imaging, it is still challenging to conduct multiplexed, brain-wide analysis with current tissue clearing techniques. Here, we propose SOLID, a hydrophobic tissue clearing method that can minimize tissue distortion while offering impressive clearing performance. SOLID achieves high-quality imaging of multi-color labeled mouse brain, and the acquired datasets can be effectively registered to the Allen Brain Atlas via commonly-used algorithms. SOLID enables generation of neural and vascular maps within one mouse brain, as well as tracing of specific neural projections labeled with viruses. SOLID also allows cross-channel investigations of ß-amyloid plaques and neurovascular lesions in the reconstructed all-in-one panorama, providing quantitative insights into structural interactions at different stages of Alzheimer's disease. Altogether, SOLID provides a robust pipeline for whole-brain mapping, which may widen the utility of tissue clearing techniques in diverse neuroscience research.
Assuntos
Doença de Alzheimer , Encéfalo , Placa Amiloide , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Animais , Camundongos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Placa Amiloide/patologia , Placa Amiloide/metabolismo , Algoritmos , Mapeamento Encefálico/métodos , Camundongos Endogâmicos C57BL , Humanos , MasculinoRESUMO
Periodontitis is a chronic inflammatory disease driven by dysbiosis in subgingival microbial communities leading to increased abundance of a limited number of pathobionts, including Porphyromonas gingivalis and Treponema denticola. Oral health, particularly periodontitis, is a modifiable risk factor for Alzheimer disease (AD) pathogenesis, with components of both these bacteria identified in postmortem brains of persons with AD. Repeated oral inoculation of mice with P. gingivalis results in brain infiltration of bacterial products, increased inflammation, and induction of AD-like biomarkers. P. gingivalis displays synergistic virulence with T. denticola during periodontitis. The aim of the current study was to determine the ability of P. gingivalis and T. denticola, grown in physiologically relevant conditions, individually and in combination, to induce AD-like pathology following chronic oral inoculation of female mice over 12 weeks. P. gingivalis alone significantly increased all 7 brain pathologies examined: neuronal damage, activation of astrocytes and microglia, expression of inflammatory cytokines interleukin 1ß (IL-1ß) and interleukin 6 and production of amyloid-ß plaques and hyperphosphorylated tau, in the hippocampus, cortex and midbrain, compared to control mice. T. denticola alone significantly increased neuronal damage, activation of astrocytes and microglia, and expression of IL-1ß, in the hippocampus, cortex and midbrain, compared to control mice. Coinoculation of P. gingivalis with T. denticola significantly increased activation of astrocytes and microglia in the hippocampus, cortex and midbrain, and increased production of hyperphosphorylated tau and IL-1ß in the hippocampus only. The host brain response elicited by oral coinoculation was less than that elicited by each bacterium, suggesting coinoculation was less pathogenic.
Assuntos
Doença de Alzheimer , Infecções por Bacteroidaceae , Encéfalo , Modelos Animais de Doenças , Porphyromonas gingivalis , Treponema denticola , Animais , Doença de Alzheimer/microbiologia , Doença de Alzheimer/patologia , Camundongos , Feminino , Encéfalo/patologia , Encéfalo/microbiologia , Infecções por Bacteroidaceae/microbiologia , Periodontite/microbiologia , Periodontite/patologia , Microglia/microbiologia , Infecções por Treponema/microbiologia , Infecções por Treponema/patologia , Camundongos Endogâmicos C57BL , Astrócitos/microbiologia , Astrócitos/patologia , Placa Amiloide/patologia , Placa Amiloide/microbiologia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Peptídeos beta-Amiloides/metabolismoRESUMO
The accumulation of ß-amyloid in Alzheimer's disease greatly impacts neuronal health and synaptic function. To maintain network stability in the face of altered synaptic activity, neurons engage a feedback mechanism termed homeostatic scaling; however, this process is thought to be disrupted during disease progression. Previous proteomics studies have shown that one of the most highly regulated proteins in cell culture models of homeostatic scaling is the small secretory chaperone proSAAS. Our prior work has shown that proSAAS exhibits anti-aggregant behavior against alpha-synuclein and ß-amyloid fibrillation in vitro and is up-regulated in cell models of proteostatic stress. However, the specific role that this protein might play in homeostatic scaling, and its anti-aggregant role in Alzheimer's progression, is not clear. To learn more about the role of proSAAS in maintaining hippocampal proteostasis, we compared its expression in a primary neuron model of homeostatic scaling to other synaptic components using western blotting and qPCR, revealing that proSAAS protein responses to homeostatic up- and down-regulation were significantly higher than those of two other synaptic vesicle components, 7B2 and carboxypeptidase E. However, proSAAS mRNA expression was static, suggesting translational control and/or altered protein degradation. ProSAAS was readily released upon depolarization of differentiated hippocampal cultures, supporting its synaptic localization. Immunohistochemical analysis demonstrated abundant proSAAS within the mossy fiber layer of the hippocampus in both wild-type and 5xFAD mice; in the latter, proSAAS was also concentrated around amyloid plaques. Importantly, overexpression of proSAAS in the CA1 region via stereotaxic injection of proSAAS-encoding AAV2/1 significantly decreased amyloid plaque burden in 5xFAD mice. We hypothesize that dynamic changes in proSAAS expression play a critical role in hippocampal proteostatic processes, both in the context of normal homeostatic plasticity and in the control of protein aggregation during Alzheimer's disease progression.
Assuntos
Doença de Alzheimer , Hipocampo , Homeostase , Camundongos Transgênicos , Placa Amiloide , Regulação para Cima , Animais , Camundongos , Hipocampo/metabolismo , Hipocampo/patologia , Placa Amiloide/patologia , Placa Amiloide/metabolismo , Homeostase/fisiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Masculino , Humanos , Camundongos Endogâmicos C57BL , Feminino , Células Cultivadas , Neurônios/metabolismo , Neurônios/patologiaRESUMO
Cotton wool plaques (CWPs) have been described as features of the neuropathologic phenotype of dominantly inherited Alzheimer disease (DIAD) caused by some missense and deletion mutations in the presenilin 1 (PSEN1) gene. CWPs are round, eosinophilic amyloid-ß (Aß) plaques that lack an amyloid core and are recognizable, but not fluorescent, in Thioflavin S (ThS) preparations. Amino-terminally truncated and post-translationally modified Aß peptide species are the main component of CWPs. Tau immunopositive neurites may be present in CWPs. In addition, neurofibrillary tangles coexist with CWPs. Herein, we report the structure of Aß and tau filaments isolated from brain tissue of individuals affected by DIAD caused by the PSEN1 V261I and A431E mutations, with the CWP neuropathologic phenotype. CWPs are predominantly composed of type I Aß filaments present in two novel arrangements, type Ic and type Id; additionally, CWPs contain type I and type Ib Aß filaments. Tau filaments have the AD fold, which has been previously reported in sporadic AD and DIAD. The formation of type Ic and type Id Aß filaments may be the basis for the phenotype of CWPs. Our data are relevant for the development of PET imaging methodologies to best detect CWPs in DIAD.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Placa Amiloide , Presenilina-1 , Proteínas tau , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Humanos , Placa Amiloide/patologia , Placa Amiloide/metabolismo , Proteínas tau/metabolismo , Proteínas tau/genética , Peptídeos beta-Amiloides/metabolismo , Presenilina-1/genética , Encéfalo/patologia , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagem , Mutação , Feminino , MasculinoRESUMO
Asymptomatic Alzheimer's disease (AsymAD) describes the status of individuals with preserved cognition but identifiable Alzheimer's disease (AD) brain pathology (i.e., beta-amyloid (Aß) deposits, neuritic plaques, and neurofibrillary tangles) at autopsy. In this study, we investigated the postmortem brains of a cohort of AsymAD subjects to gain insight into the mechanisms underlying resilience to AD pathology and cognitive decline. Our results showed that AsymAD cases exhibit enrichment in core plaques, decreased filamentous plaque accumulation, and increased plaque-surrounding microglia. Less pathological tau aggregation in dystrophic neurites was found in AsymAD brains than in AD brains, and tau seeding activity was comparable to that in healthy brains. We used spatial transcriptomics to characterize the plaque niche further and revealed autophagy, endocytosis, and phagocytosis as the pathways associated with the genes upregulated in the AsymAD plaque niche. Furthermore, the levels of ARP2 and CAP1, which are actin-based motility proteins that participate in the dynamics of actin filaments to allow cell motility, were increased in the microglia surrounding amyloid plaques in AsymAD cases. Our findings suggest that the amyloid-plaque microenvironment in AsymAD cases is characterized by the presence of microglia with highly efficient actin-based cell motility mechanisms and decreased tau seeding compared with that in AD brains. These two mechanisms can potentially protect against the toxic cascade initiated by Aß, preserving brain health, and slowing AD pathology progression.
Assuntos
Doença de Alzheimer , Microglia , Placa Amiloide , Proteínas tau , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Humanos , Microglia/metabolismo , Microglia/patologia , Placa Amiloide/patologia , Placa Amiloide/metabolismo , Proteínas tau/metabolismo , Idoso , Masculino , Idoso de 80 Anos ou mais , Feminino , Encéfalo/patologia , Encéfalo/metabolismo , Reserva Cognitiva/fisiologia , Peptídeos beta-Amiloides/metabolismo , Emaranhados Neurofibrilares/patologia , Emaranhados Neurofibrilares/metabolismoRESUMO
AIMS: Microglial cells are integral to the pathogenesis of Alzheimer's disease (AD). The observed sex disparity in AD prevalence, with a notable predominance in women, implies a potential influence of sex hormones, such as androgens, on disease mechanisms. Despite this, the specific effects of androgens on microglia remain unclear. This study is designed to delineate the interplay between androgens and the survival and inflammatory profile of microglial cells, as well as to explore their contribution to the progression of AD. METHODS AND KEY FINDINGS: To create a chronic androgen deficiency model, 3-month-old wild-type (WT) mice and APP/PS1 mice underwent bilateral orchiectomy (ORX), with age-matched sham-operated controls. Cognitive and memory were evaluated at 5 and 12 months, paralleled by assessments of amyloid-beta (Aß) and microglial morphology in hippocampal and cortical areas. The ORX treatment in mice resulted in diminished microglial populations and morphological alterations, alongside an increase in Aß plaques and a concomitant decline in cognitive performance that exacerbated over time. In vitro, dihydrotestosterone (DHT) was found to stimulate microglial proliferation and ameliorate Aß1-42-induced apoptosis. SIGNIFICANCE: These findings suggested that androgens may exert a protective role, maintaining the normal proliferation and functionality of microglial cells. This preservation could potentially slow the progression of AD. As a result, our study provided a conceptual framework for the development of novel therapeutic strategies for AD.
Assuntos
Doença de Alzheimer , Androgênios , Camundongos Transgênicos , Microglia , Animais , Microglia/patologia , Microglia/metabolismo , Microglia/efeitos dos fármacos , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Masculino , Camundongos , Androgênios/farmacologia , Androgênios/metabolismo , Androgênios/deficiência , Orquiectomia , Peptídeos beta-Amiloides/metabolismo , Camundongos Endogâmicos C57BL , Di-Hidrotestosterona/farmacologia , Modelos Animais de Doenças , Hipocampo/patologia , Hipocampo/metabolismo , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fatores Etários , Placa Amiloide/patologia , Placa Amiloide/metabolismoRESUMO
Episodic memory in older adults is varied and perceived to rely on numbers of synapses or dendritic spines. We analyzed 2157 neurons among 128 older individuals from the Religious Orders Study and Rush Memory and Aging Project. Analysis of 55,521 individual dendritic spines by least absolute shrinkage and selection operator regression and nested model cross-validation revealed that the dendritic spine head diameter in the temporal cortex, but not the premotor cortex, improved the prediction of episodic memory performance in models containing ß amyloid plaque scores, neurofibrillary tangle pathology, and sex. These findings support the emerging hypothesis that, in the temporal cortex, synapse strength is more critical than quantity for memory in old age.
Assuntos
Espinhas Dendríticas , Memória Episódica , Humanos , Espinhas Dendríticas/fisiologia , Masculino , Feminino , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Lobo Temporal/fisiologia , Placa Amiloide/patologiaRESUMO
Accurate and scalable quantification of amyloid-ß (Aß) pathology is crucial for deeper disease phenotyping and furthering research in Alzheimer Disease (AD). This multidisciplinary study addresses the current limitations on neuropathology by leveraging a machine learning (ML) pipeline to perform a granular quantification of Aß deposits and assess their distribution in the temporal lobe. Utilizing 131 whole-slide-images from consecutive autopsied cases at the University of California Davis Alzheimer Disease Research Center, our objectives were threefold: (1) Validate an automatic workflow for Aß deposit quantification in white matter (WM) and gray matter (GM); (2) define the distributions of different Aß deposit types in GM and WM, and (3) investigate correlates of Aß deposits with dementia status and the presence of mixed pathology. Our methodology highlights the robustness and efficacy of the ML pipeline, demonstrating proficiency akin to experts' evaluations. We provide comprehensive insights into the quantification and distribution of Aß deposits in the temporal GM and WM revealing a progressive increase in tandem with the severity of established diagnostic criteria (NIA-AA). We also present correlations of Aß load with clinical diagnosis as well as presence/absence of mixed pathology. This study introduces a reproducible workflow, showcasing the practical use of ML approaches in the field of neuropathology, and use of the output data for correlative analyses. Acknowledging limitations, such as potential biases in the ML model and current ML classifications, we propose avenues for future research to refine and expand the methodology. We hope to contribute to the broader landscape of neuropathology advancements, ML applications, and precision medicine, paving the way for deep phenotyping of AD brain cases and establishing a foundation for further advancements in neuropathological research.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Aprendizado de Máquina , Lobo Temporal , Humanos , Lobo Temporal/patologia , Lobo Temporal/metabolismo , Peptídeos beta-Amiloides/metabolismo , Feminino , Masculino , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Bancos de Tecidos , Substância Cinzenta/patologia , Substância Cinzenta/metabolismo , Substância Branca/patologia , Substância Branca/metabolismo , Placa Amiloide/patologia , Placa Amiloide/metabolismo , Pessoa de Meia-IdadeRESUMO
Alzheimer's disease (AD) is linked to toxic Aß plaques in the brain and activation of innate responses. Recent findings however suggest that the disease may also depend on the adaptive immunity, as B cells exacerbate and CD8+ T cells limit AD-like pathology in mouse models of amyloidosis. Here, by artificially blocking or augmenting CD8+ T cells in the brain of 5xFAD mice, we provide evidence that AD-like pathology is promoted by pathogenic, proinflammatory cytokines and exhaustion markers expressing CXCR6+ CD39+CD73+/- CD8+ TRM-like cells. The CD8+ T cells appear to act by targeting disease associated microglia (DAM), as we find them in tight complexes with microglia around Aß plaques in the brain of mice and humans with AD. We also report that these CD8+ T cells are induced by B cells in the periphery, further underscoring the pathogenic importance of the adaptive immunity in AD. We propose that CD8+ T cells and B cells should be considered as therapeutic targets for control of AD, as their ablation at the onset of AD is sufficient to decrease CD8+ T cells in the brain and block the amyloidosis-linked neurodegeneration.
Assuntos
Doença de Alzheimer , Amiloidose , Encéfalo , Linfócitos T CD8-Positivos , Modelos Animais de Doenças , Microglia , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Camundongos , Amiloidose/imunologia , Doença de Alzheimer/imunologia , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Encéfalo/imunologia , Encéfalo/patologia , Encéfalo/metabolismo , Microglia/imunologia , Microglia/metabolismo , Camundongos Transgênicos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Humanos , Placa Amiloide/imunologia , Placa Amiloide/patologia , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/imunologia , Imunidade Adaptativa/imunologia , Citocinas/metabolismo , Feminino , Camundongos Endogâmicos C57BL , MasculinoRESUMO
Levites et al. demonstrate that mouse models of Alzheimer disease (AD), exhibiting amyloid-beta (Αß) plaque formation, share Αß responsome proteins with humans. Their work underscores the value of these models in studying Αß aggregation, cellular vulnerability, and early-stage AD pathology.
Assuntos
Doença de Alzheimer , Modelos Animais de Doenças , Proteoma , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Animais , Humanos , Proteoma/metabolismo , Camundongos , Peptídeos beta-Amiloides/metabolismo , Placa Amiloide/patologia , Placa Amiloide/metabolismoRESUMO
Amyloid-ß (Aß) is thought to be neuronally derived in Alzheimer's disease (AD). However, transcripts of amyloid precursor protein (APP) and amyloidogenic enzymes are equally abundant in oligodendrocytes (OLs). By cell-type-specific deletion of Bace1 in a humanized knock-in AD model, APPNLGF, we demonstrate that OLs and neurons contribute to Aß plaque burden. For rapid plaque seeding, excitatory projection neurons must provide a threshold level of Aß. Ultimately, our findings are relevant for AD prevention and therapeutic strategies.
Assuntos
Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides , Ácido Aspártico Endopeptidases , Neurônios , Oligodendroglia , Placa Amiloide , Animais , Humanos , Camundongos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Modelos Animais de Doenças , Camundongos Transgênicos , Neurônios/metabolismo , Neurônios/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Placa Amiloide/patologia , Placa Amiloide/metabolismoRESUMO
Alzheimer's disease (AD) is a complex neurodegenerative disorder that develops over decades. AD brain proteomics reveals vast alterations in protein levels and numerous altered biologic pathways. Here, we compare AD brain proteome and network changes with the brain proteomes of amyloid ß (Aß)-depositing mice to identify conserved and divergent protein networks with the conserved networks identifying an Aß amyloid responsome. Proteins in the most conserved network (M42) accumulate in plaques, cerebrovascular amyloid (CAA), and/or dystrophic neuronal processes, and overexpression of two M42 proteins, midkine (Mdk) and pleiotrophin (PTN), increases the accumulation of Aß in plaques and CAA. M42 proteins bind amyloid fibrils in vitro, and MDK and PTN co-accumulate with cardiac transthyretin amyloid. M42 proteins appear intimately linked to amyloid deposition and can regulate amyloid deposition, suggesting that they are pathology modifiers and thus putative therapeutic targets. We posit that amyloid-scaffolded accumulation of numerous M42+ proteins is a central mechanism mediating downstream pathophysiology in AD.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Encéfalo , Placa Amiloide , Proteômica , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Proteômica/métodos , Animais , Peptídeos beta-Amiloides/metabolismo , Humanos , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Camundongos , Encéfalo/metabolismo , Encéfalo/patologia , Proteoma/metabolismo , Camundongos Transgênicos , Proteínas de Transporte/metabolismo , Proteínas de Transporte/genética , Citocinas/metabolismo , MasculinoRESUMO
Alzheimer's disease is the primary neurodegenerative disease affecting the elderly population. Despite the first description of its pathology over a century ago, its precise cause and molecular mechanism remain unknown. Numerous factors, including beta-amyloid, tau protein, the APOEε4 gene, and different metals, have been extensively investigated in relation to this disease. However, none of them have been proven to have a decisive causal relationship. Furthermore, no single theory has successfully integrated these puzzle pieces thus far. In this review article, we propose the most probable molecular mechanism for AD, which clearly shows the relationship between the main aspects of the disease, and addresses fundamental questions such as: Why is aging the major risk factor for the disease? Are amyloid plaques and tau tangles the causes or consequences of AD? Why are the distributions of senile plaques and tau tangles in the brain different and independent of each other? Why is the APOEε4 gene a risk factor for AD? Finally, why is the disease more prevalent in women?
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Proteínas tau , Humanos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Proteínas tau/metabolismo , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Fatores de RiscoRESUMO
Human brain aging is characterized by the production and deposition of ß-amyloid (Aß) in the form of senile plaques and cerebral amyloid angiopathy and the intracellular accumulation of hyper-phosphorylated tau (Hp-tau) to form neurofibrillary tangles (NFTs) and dystrophic neurites of senile plaques. The process progresses for years and eventually manifests as cognitive impairment and dementia in a subgroup of aged individuals. Aß is produced and deposited first in the neocortex in most aged mammals, including humans; it is usually not accompanied by altered behavior and cognitive impairment. Hp-tau is less frequent than Aß pathology, and NFTs are rare in most mammals. In contrast, NFTs are familiar from middle age onward in humans; NFTs first appear in the paleocortex and selected brain stem nuclei. NFTs precede for decades or years Aß deposition and correlate with dementia in about 5% of individuals at the age of 65 and 25% at the age of 85. Based on these comparative data, (a) Aß deposition is the most common Alzheimer's disease neuropathological change (ADNC) in the brain of aged mammals; (b) Hp-tau is less common, and NFTs are rare in most aged mammals; however, NFTs are the principal cytoskeletal pathology in aged humans; (c) NFT in aged humans starts in selected nuclei of the brain stem and paleocortical brain regions progressing to the most parts of the neocortex and other regions of the telencephalon; (d) human brain aging is unique among mammalian species due to the early appearance and dramatic progression of NFTs from middle age onward, matching with cognitive impairment and dementia in advanced cases; (e) neither mammalian nor human brain aging supports the concept of the amyloid cascade hypothesis.
Assuntos
Envelhecimento , Doença de Alzheimer , Emaranhados Neurofibrilares , Proteínas tau , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Animais , Humanos , Envelhecimento/patologia , Envelhecimento/metabolismo , Emaranhados Neurofibrilares/patologia , Emaranhados Neurofibrilares/metabolismo , Proteínas tau/metabolismo , Encéfalo/patologia , Encéfalo/metabolismo , Peptídeos beta-Amiloides/metabolismo , Mamíferos/metabolismo , Placa Amiloide/patologia , Placa Amiloide/metabolismoRESUMO
Besides its two defining misfolded proteinopathies-Aß plaques and tau neurofibrillary tangles-Alzheimer's disease (AD) is an exemplar of a neurodegenerative disease with prominent reactive astrogliosis, defined as the set of morphological, molecular, and functional changes that astrocytes suffer as the result of a toxic exposure. Reactive astrocytes can be observed in the vicinity of plaques and tangles, and the relationship between astrocytes and these AD neuropathological lesions is bidirectional so that each AD neuropathological hallmark causes specific changes in astrocytes, and astrocytes modulate the severity of each neuropathological feature in a specific manner. Here, we will review both how astrocytes change as a result of their chronic exposure to AD neuropathology and how those astrocytic changes impact each AD neuropathological feature. We will emphasize the repercussions that AD-associated reactive astrogliosis has for the astrocyte-neuron interaction and highlight areas of uncertainty and priorities for future research.