RESUMEN
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.
Asunto(s)
Amiloide , Aprendizaje Profundo , Microscopía Fluorescente , Coloración y Etiquetado , Humanos , Birrefringencia , Amiloide/metabolismo , Microscopía Fluorescente/métodos , Coloración y Etiquetado/métodos , Rojo Congo , Microscopía de Polarización/métodos , Amiloidosis/patología , Amiloidosis/metabolismo , Amiloidosis/diagnóstico por imagen , Imagen Óptica/métodos , Placa Amiloide/patología , Placa Amiloide/metabolismo , Placa Amiloide/diagnóstico por imagen , Miocardio/patología , Miocardio/metabolismoRESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer , Encéfalo , Modelos Animales de Enfermedad , Ratones Transgénicos , Toxoplasma , Animales , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/parasitología , Enfermedad de Alzheimer/patología , Ratones , Encéfalo/parasitología , Encéfalo/metabolismo , Encéfalo/patología , Péptidos beta-Amiloides/metabolismo , Placa Amiloide/metabolismo , Placa Amiloide/patología , Toxoplasmosis/metabolismo , FemeninoRESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer , Infecciones por Bacteroidaceae , Encéfalo , Modelos Animales de Enfermedad , Porphyromonas gingivalis , Treponema denticola , Animales , Enfermedad de Alzheimer/microbiología , Enfermedad de Alzheimer/patología , Ratones , Femenino , Encéfalo/patología , Encéfalo/microbiología , Infecciones por Bacteroidaceae/microbiología , Periodontitis/microbiología , Periodontitis/patología , Microglía/microbiología , Infecciones por Treponema/microbiología , Infecciones por Treponema/patología , Ratones Endogámicos C57BL , Astrocitos/microbiología , Astrocitos/patología , Placa Amiloide/patología , Placa Amiloide/microbiología , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Péptidos beta-Amiloides/metabolismoRESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer , Andrógenos , Ratones Transgénicos , Microglía , Animales , Microglía/patología , Microglía/metabolismo , Microglía/efectos de los fármacos , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Masculino , Ratones , Andrógenos/farmacología , Andrógenos/metabolismo , Andrógenos/deficiencia , Orquiectomía , Péptidos beta-Amiloides/metabolismo , Ratones Endogámicos C57BL , Dihidrotestosterona/farmacología , Modelos Animales de Enfermedad , Hipocampo/patología , Hipocampo/metabolismo , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Factores de Edad , Placa Amiloide/patología , Placa Amiloide/metabolismoRESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer , Astrocitos , Neuronas , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Astrocitos/metabolismo , Astrocitos/patología , Humanos , Neuronas/metabolismo , Neuronas/patología , Gliosis/metabolismo , Gliosis/patología , Ovillos Neurofibrilares/metabolismo , Ovillos Neurofibrilares/patología , Placa Amiloide/metabolismo , Placa Amiloide/patología , Comunicación Celular/fisiología , Proteínas tau/metabolismo , Péptidos beta-Amiloides/metabolismo , AnimalesRESUMEN
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.
Asunto(s)
Espinas Dendríticas , Memoria Episódica , Humanos , Espinas Dendríticas/fisiología , Masculino , Femenino , Anciano , Anciano de 80 o más Años , Envejecimiento/fisiología , Lóbulo Temporal/fisiología , Placa Amiloide/patologíaRESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Aprendizaje Automático , Lóbulo Temporal , Humanos , Lóbulo Temporal/patología , Lóbulo Temporal/metabolismo , Péptidos beta-Amiloides/metabolismo , Femenino , Masculino , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Bancos de Tejidos , Sustancia Gris/patología , Sustancia Gris/metabolismo , Sustancia Blanca/patología , Sustancia Blanca/metabolismo , Placa Amiloide/patología , Placa Amiloide/metabolismo , Persona de Mediana EdadRESUMEN
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.
Asunto(s)
Envejecimiento , Enfermedad de Alzheimer , Ovillos Neurofibrilares , Proteínas tau , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Animales , Humanos , Envejecimiento/patología , Envejecimiento/metabolismo , Ovillos Neurofibrilares/patología , Ovillos Neurofibrilares/metabolismo , Proteínas tau/metabolismo , Encéfalo/patología , Encéfalo/metabolismo , Péptidos beta-Amiloides/metabolismo , Mamíferos/metabolismo , Placa Amiloide/patología , Placa Amiloide/metabolismoRESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer , Microglía , Placa Amiloide , Proteínas tau , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Humanos , Microglía/metabolismo , Microglía/patología , Placa Amiloide/patología , Placa Amiloide/metabolismo , Proteínas tau/metabolismo , Anciano , Masculino , Anciano de 80 o más Años , Femenino , Encéfalo/patología , Encéfalo/metabolismo , Reserva Cognitiva/fisiología , Péptidos beta-Amiloides/metabolismo , Ovillos Neurofibrilares/patología , Ovillos Neurofibrilares/metabolismoRESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer , Amiloidosis , Encéfalo , Linfocitos T CD8-positivos , Modelos Animales de Enfermedad , Microglía , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Ratones , Amiloidosis/inmunología , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Encéfalo/inmunología , Encéfalo/patología , Encéfalo/metabolismo , Microglía/inmunología , Microglía/metabolismo , Ratones Transgénicos , Linfocitos B/inmunología , Linfocitos B/metabolismo , Humanos , Placa Amiloide/inmunología , Placa Amiloide/patología , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/inmunología , Inmunidad Adaptativa/inmunología , Citocinas/metabolismo , Femenino , Ratones Endogámicos C57BL , MasculinoRESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer , Modelos Animales de Enfermedad , Proteoma , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Animales , Humanos , Proteoma/metabolismo , Ratones , Péptidos beta-Amiloides/metabolismo , Placa Amiloide/patología , Placa Amiloide/metabolismoRESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer , Secretasas de la Proteína Precursora del Amiloide , Péptidos beta-Amiloides , Ácido Aspártico Endopeptidasas , Neuronas , Oligodendroglía , Placa Amiloide , Animales , Humanos , Ratones , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Modelos Animales de Enfermedad , Ratones Transgénicos , Neuronas/metabolismo , Neuronas/patología , Oligodendroglía/metabolismo , Oligodendroglía/patología , Placa Amiloide/patología , Placa Amiloide/metabolismoRESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Encéfalo , Placa Amiloide , Proteómica , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Proteómica/métodos , Animales , Péptidos beta-Amiloides/metabolismo , Humanos , Placa Amiloide/metabolismo , Placa Amiloide/patología , Ratones , Encéfalo/metabolismo , Encéfalo/patología , Proteoma/metabolismo , Ratones Transgénicos , Proteínas Portadoras/metabolismo , Proteínas Portadoras/genética , Citocinas/metabolismo , MasculinoRESUMEN
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?
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Proteínas tau , Humanos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Proteínas tau/metabolismo , Placa Amiloide/metabolismo , Placa Amiloide/patología , Animales , Encéfalo/metabolismo , Encéfalo/patología , Factores de RiesgoRESUMEN
The anterior thalamic nuclei are important for cognition, and memory in particular. However, little is known about how the anterior thalamic nuclei are affected in many neurological disorders partly due to difficulties in selective segmentation in in vivo scans, due to their size and location. Post-mortem studies, therefore, remain a valuable source of information about the status of the anterior thalamic nuclei. We used post-mortem tissue to assess the status of the anteroventral thalamic nucleus in Down syndrome using samples from males and females ranging from 22-65 years in age and comparing to tissue from age matched controls. As expected, there was increased beta-amyloid plaque expression in the Down syndrome group. While there was a significant increase in neuronal density in the Down syndrome group, the values showed more variation consistent with a heterogeneous population. The surface area of the anteroventral thalamic nucleus was smaller in the Down syndrome group suggesting the increased neuronal density was due to greater neuronal packing but likely fewer overall neurons. There was a marked reduction in the proportion of neurons immunoreactive for the calcium-binding proteins calbindin, calretinin, and parvalbumin in individuals with Down syndrome. These findings highlight the vulnerability of calcium-binding proteins in the anteroventral nucleus in Down syndrome, which could both be driven by, and exacerbate, Alzheimer-related pathology in this region.
Asunto(s)
Núcleos Talámicos Anteriores , Síndrome de Down , Neuronas , Humanos , Síndrome de Down/metabolismo , Síndrome de Down/patología , Masculino , Femenino , Persona de Mediana Edad , Adulto , Anciano , Núcleos Talámicos Anteriores/metabolismo , Núcleos Talámicos Anteriores/patología , Neuronas/metabolismo , Neuronas/patología , Adulto Joven , Proteínas de Unión al Calcio/metabolismo , Parvalbúminas/metabolismo , Placa Amiloide/metabolismo , Placa Amiloide/patologíaRESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Placa Amiloide , Presenilina-1 , Proteínas tau , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Humanos , Placa Amiloide/patología , Placa Amiloide/metabolismo , Proteínas tau/metabolismo , Proteínas tau/genética , Péptidos beta-Amiloides/metabolismo , Presenilina-1/genética , Encéfalo/patología , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Mutación , Femenino , MasculinoRESUMEN
Senile plaques, mainly diffuse, and cerebral amyloid-ß (Aß) angiopathy are prevalent in the aging brain of non-human primates, from lemurs to non-human Hominidae. Aß but not hyper-phosphorylated tau (HPtau) pathology is the common nominator proteinopathy of non-human primate brain aging. The abundance of Aß in the aging primate brain is well tolerated, and the impact on cognitive functions is usually limited to particular tasks. In contrast, human brain aging is characterized by the early appearance of HPtau pathology, mainly forming neurofibrillary tangles, dystrophic neurites of neuritic plaques, and neuropil threads, preceding Aß deposits by several decades and by its severity progressing from selected nuclei of the brain stem, entorhinal cortex, and hippocampus to the limbic system, neocortex, and other brain regions. Neurofibrillary tangles correlate with cognitive impairment and dementia in advanced cases. Aß pathology is linked in humans to altered membrane protein and lipid composition, particularly involving lipid rafts. Although similar membrane alterations are unknown in non-human primates, membrane senescence is postulated to cause the activated ß-amyloidogenic pathway, and Aß pathology is the prevailing signature of non-human and human primate brain aging.
Asunto(s)
Envejecimiento , Péptidos beta-Amiloides , Encéfalo , Primates , Animales , Envejecimiento/patología , Envejecimiento/metabolismo , Encéfalo/patología , Encéfalo/metabolismo , Péptidos beta-Amiloides/metabolismo , Humanos , Ovillos Neurofibrilares/patología , Placa Amiloide/patología , Proteínas tau/metabolismoRESUMEN
The diagnostic value of imaging Aß plaques in Alzheimer's disease (AD) has accelerated the development of fluorine-18 labeled radiotracers with a longer half-life for easier translation to clinical use. We have developed [18F]flotaza, which shows high binding to Aß plaques in postmortem human AD brain slices with low white matter binding. We report the binding of [18F]flotaza in postmortem AD hippocampus compared to cognitively normal (CN) brains and the evaluation of [18F]flotaza in transgenic 5xFAD mice expressing Aß plaques. [18F]Flotaza binding was assessed in well-characterized human postmortem brain tissue sections consisting of HP CA1-subiculum (HP CA1-SUB) regions in AD (n = 28; 13 male and 15 female) and CN subjects (n = 32; 16 male and 16 female). Adjacent slices were immunostained with anti-Aß and analyzed using QuPath. In vitro and in vivo [18F]flotaza PET/CT studies were carried out in 5xFAD mice. Post-mortem human brain slices from all AD subjects were positively IHC stained with anti-Aß. High [18F]flotaza binding was measured in the HP CA1-SUB grey matter (GM) regions compared to white matter (WM) of AD subjects with GM/WM > 100 in some subjects. The majority of CN subjects had no decipherable binding. Male AD exhibited greater WM than AD females (AD WMâ/WMâ > 5; p < 0.001) but no difference amongst CN WM. In vitro studies in 5xFAD mice brain slices exhibited high binding [18F]flotaza ratios (>50 versus cerebellum) in the cortex, HP, and thalamus. In vivo, PET [18F]flotaza exhibited binding to Aß plaques in 5xFAD mice with SUVR~1.4. [18F]Flotaza is a new Aß plaque PET imaging agent that exhibited high binding to Aß plaques in postmortem human AD. Along with the promising results in 5xFAD mice, the translation of [18F]flotaza to human PET studies may be worthwhile.
Asunto(s)
Enfermedad de Alzheimer , Radioisótopos de Flúor , Hipocampo , Placa Amiloide , Tomografía Computarizada por Tomografía de Emisión de Positrones , Anciano , Anciano de 80 o más Años , Animales , Femenino , Humanos , Masculino , Ratones , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Autopsia , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Hipocampo/diagnóstico por imagen , Hipocampo/metabolismo , Hipocampo/patología , Ratones Transgénicos , Placa Amiloide/diagnóstico por imagen , Placa Amiloide/metabolismo , Placa Amiloide/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Piridinas , Pirrolidinonas , Radiofármacos/farmacocinéticaRESUMEN
Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by the accumulation of amyloid-ß (Aß) plaques, neuroinflammation, and neuronal death. Besides aging, various comorbidities increase the risk of AD, including obesity, diabetes, and allergic asthma. Epidemiological studies have reported a 2.17-fold higher risk of dementia in asthmatic patients. However, the molecular mechanism(s) underlying this asthma-associated AD exacerbation is unknown. This study was designed to explore house dust mite (HDM)-induced asthma effects on AD-related brain changes using the AppNL-G-F transgenic mouse model of disease. Male and female 8-9 months old C57BL/6J wild type and AppNL-G-F mice were exposed to no treatment, saline sham, or HDM extract every alternate day for 16 weeks for comparison across genotypes and treatment. Mice were euthanized at the end of the experiment, and broncho-alveolar lavage fluid (BALF), blood, lungs, and brains were collected. BALF was used to quantify immune cell phenotype, cytokine levels, total protein content, lactate dehydrogenase (LDH) activity, and total IgE. Lungs were sectioned and stained with hematoxylin and eosin, Alcian blue, and Masson's trichrome. Serum levels of cytokines and soluble Aß1-40/42 were quantified. Brains were sectioned and immunostained for Aß, GFAP, CD68, and collagen IV. Finally, frozen hippocampi and temporal cortices were used to perform Aß ELISAs and cytokine arrays, respectively. HDM exposure led to increased levels of inflammatory cells, cytokines, total protein content, LDH activity, and total IgE in the BALF, as well as increased pulmonary mucus and collagen staining in both sexes and genotypes. Levels of serum cytokines increased in all HDM-exposed groups. Serum from the AppNL-G-F HDM-induced asthma group also had significantly increased soluble Aß1-42 levels in both sexes. In agreement with this peripheral change, hippocampi from asthma-induced male and female AppNL-G-F mice demonstrated elevated Aß plaque load and increased soluble Aß 1-40/42 and insoluble Aß 1-40 levels. HDM exposure also increased astrogliosis and microgliosis in both sexes of AppNL-G-F mice, as indicated by GFAP and CD68 immunoreactivity, respectively. Additionally, HDM exposure elevated cortical levels of several cytokines in both sexes and genotypes. Finally, HDM-exposed groups also showed a disturbed blood-brain-barrier (BBB) integrity in the hippocampus of AppNL-G-F mice, as indicated by decreased collagen IV immunoreactivity. HDM exposure was responsible for an asthma-like condition in the lungs that exacerbated Aß pathology, astrogliosis, microgliosis, and cytokine changes in the brains of male and female AppNL-G-F mice that correlated with reduced BBB integrity. Defining mechanisms of asthma effects on the brain may identify novel therapeutic targets for asthma and AD.