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Background: Alzheimer's disease (AD) is characterized by the presence of neurofibrillary tangles made of hyperphosphorylated tau and senile plaques composed of beta-amyloid. These pathognomonic deposits have been implicated in the pathogenesis, although the molecular mechanisms and consequences remain undetermined. UFM1 is an important, but understudied ubiquitin-like protein that is covalently attached to substrates. This UFMylation has recently been identified as major modifier of tau aggregation upon seeding in experimental models. However, potential alterations of the UFM1 pathway in human AD brain have not been investigated yet. Methods: Here we used frontal and temporal cortex samples from individuals with or without AD to measure the protein levels of the UFMylation pathway in human brain. We used multivariable regression analyses followed by Bonferroni correction for multiple testing to analyze associations of the UFMylation pathway with neuropathological characteristics, primary biochemical measurements of tau and additional biochemical markers from the same cases. We further studied associations of the UFMylation cascade with cellular stress pathways using Spearman correlations with bulk RNAseq expression data and functionally validated these interactions using gene-edited neurons that were generated by CRISPR-Cas9. Results: Compared to controls, human AD brain had increased protein levels of UFM1. Our data further indicates that this increase mainly reflects conjugated UFM1 indicating hyperUFMylation in AD. UFMylation was strongly correlated with pathological tau in both AD-affected brain regions. In addition, we found that the levels of conjugated UFM1 were negatively correlated with soluble levels of the deUFMylation enzyme UFSP2. Functional analysis of UFM1 and/or UFSP2 knockout neurons revealed that the DNA damage response as well as the unfolded protein response are perturbed by changes in neuronal UFM1 signaling. Conclusions: There are marked changes in the UFMylation pathway in human AD brain. These changes are significantly associated with pathological tau, supporting the idea that the UFMylation cascade might indeed act as a modifier of tau pathology in human brain. Our study further nominates UFSP2 as an attractive target to reduce the hyperUFMylation observed in AD brain but also underscores the critical need to identify risks and benefits of manipulating the UFMylation pathway as potential therapeutic avenue for AD.
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Microglia replacement strategies are increasingly being considered for the treatment of primary microgliopathies like adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). However, available mouse models fail to recapitulate the diverse neuropathologies and reduced microglia numbers observed in patients. In this study, we generated a xenotolerant mouse model lacking the fms-intronic regulatory element (FIRE) enhancer within Csf1r, which develops nearly all the hallmark pathologies associated with ALSP. Remarkably, transplantation of human induced pluripotent stem cell (iPSC)-derived microglial (iMG) progenitors restores a homeostatic microglial signature and prevents the development of axonal spheroids, white matter abnormalities, reactive astrocytosis, and brain calcifications. Furthermore, transplantation of CRISPR-corrected ALSP-patient-derived iMG reverses pre-existing spheroids, astrogliosis, and calcification pathologies. Together with the accompanying study by Munro and colleagues, our results demonstrate the utility of FIRE mice to model ALSP and provide compelling evidence that iMG transplantation could offer a promising new therapeutic strategy for ALSP and perhaps other microglia-associated neurological disorders.
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The immune system substantially influences age-related cognitive decline and Alzheimer's disease (AD) progression, affected by genetic and environmental factors. In a Mayo Clinic Study of Aging cohort, we examined how risk factors like APOE genotype, age, and sex affect inflammatory molecules and AD biomarkers in cerebrospinal fluid (CSF). Among cognitively unimpaired individuals over 65 (N = 298), we measured 365 CSF inflammatory molecules, finding age, sex, and diabetes status predominantly influencing their levels. We observed age-related correlations with AD biomarkers such as total tau, phosphorylated tau-181, neurofilament light chain (NfL), and YKL40. APOE4 was associated with lower Aß42 and higher SNAP25 in CSF. We explored baseline variables predicting cognitive decline risk, finding age, CSF Aß42, NfL, and REG4 to be independently correlated. Subjects with older age, lower Aß42, higher NfL, and higher REG4 at baseline had increased cognitive impairment risk during follow-up. This suggests that assessing CSF inflammatory molecules and AD biomarkers could predict cognitive impairment risk in the elderly.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Anciano , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/líquido cefalorraquídeo , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/etiología , Proteínas tau , Biomarcadores , Péptidos beta-Amiloides , Fragmentos de PéptidosRESUMEN
Alzheimer's disease (AD), characterized by the deposition of amyloid-ß (Aß) in senile plaques and neurofibrillary tangles of phosphorylated tau (pTau), is increasingly recognized as a complex disease with multiple pathologies. AD sometimes pathologically overlaps with age-related tauopathies such as four repeat (4R)-tau predominant argyrophilic grain disease (AGD). While AGD is often detected with AD pathology, the contribution of APOE4 to AGD risk is not clear despite its robust effects on AD pathogenesis. Specifically, how APOE genotype influences Aß and tau pathology in co-occurring AGD and AD has not been fully understood. Using postmortem brain samples (N = 353) from a neuropathologically defined cohort comprising of cases with AD and/or AGD pathology built to best represent different APOE genotypes, we measured the amounts of major AD-related molecules, including Aß40, Aß42, apolipoprotein E (apoE), total tau (tTau), and pTau181, in the temporal cortex. The presence of tau lesions characteristic of AD (AD-tau) was correlated with cognitive decline based on Mini-Mental State Examination (MMSE) scores, while the presence of AGD tau lesions (AGD-tau) was not. Interestingly, while APOE4 increased the risk of AD-tau pathology, it did not increase the risk of AGD-tau pathology. Although APOE4 was significantly associated with higher levels of insoluble Aß40, Aß42, apoE, and pTau181, the APOE4 effect was no longer detected in the presence of AGD-tau. We also found that co-occurrence of AGD with AD was associated with lower insoluble Aß42 and pTau181 levels. Overall, our findings suggest that different patterns of Aß, tau, and apoE accumulation mediate the development of AD-tau and AGD-tau pathology, which is affected by APOE genotype.
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Enfermedad de Alzheimer , Apolipoproteínas E , Tauopatías , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Amiloide , Péptidos beta-Amiloides , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Proteínas tau , Tauopatías/patologíaRESUMEN
OBJECTIVE: This study was undertaken to apply established and emerging cerebrospinal fluid (CSF) biomarkers to improve diagnostic accuracy in patients with rapidly progressive dementia (RPD). Overlap in clinical presentation and results of diagnostic tests confounds etiologic diagnosis in patients with RPD. Objective measures are needed to improve diagnostic accuracy and to recognize patients with potentially treatment-responsive causes of RPD. METHODS: Biomarkers of Alzheimer disease neuropathology (amyloid-ß 42/40 ratio, phosphorylated tau [p-tau181, p-tau231]), neuroaxonal/neuronal injury (neurofilament light chain [NfL], visinin-like protein-1 [VILIP-1], total tau), neuroinflammation (chitinase-3-like protein [YKL-40], soluble triggering receptor expressed on myeloid cells 2 [sTREM2], glial fibrillary acidic protein [GFAP], monocyte chemoattractant protein-1 [MCP-1]), and synaptic dysfunction (synaptosomal-associated protein 25kDa, neurogranin) were measured in CSF obtained at presentation from 78 prospectively accrued patients with RPD due to neurodegenerative, vascular, and autoimmune/inflammatory diseases; 35 age- and sex-matched patients with typically progressive neurodegenerative disease; and 72 cognitively normal controls. Biomarker levels were compared across etiologic diagnoses, by potential treatment responsiveness, and between patients with typical and rapidly progressive presentations of neurodegenerative disease. RESULTS: Alzheimer disease biomarkers were associated with neurodegenerative causes of RPD. High NfL, sTREM2, and YKL-40 and low VILIP-1 identified patients with autoimmune/inflammatory diseases. MCP-1 levels were highest in patients with vascular causes of RPD. A multivariate model including GFAP, MCP-1, p-tau181, and sTREM2 identified the 44 patients with treatment-responsive causes of RPD with 89% accuracy. Minimal differences were observed between typical and rapidly progressive presentations of neurodegenerative disease. INTERPRETATION: Selected CSF biomarkers at presentation were associated with etiologic diagnoses and treatment responsiveness in patients with heterogeneous causes of RPD. The ability of cross-sectional biomarkers to inform upon mechanisms that drive rapidly progressive neurodegenerative disease is less clear. ANN NEUROL 2024;95:299-313.
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Enfermedad de Alzheimer , Demencia , Enfermedades Neurodegenerativas , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/líquido cefalorraquídeo , Proteína 1 Similar a Quitinasa-3 , Proteínas tau/líquido cefalorraquídeo , Estudios Transversales , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeoRESUMEN
ABCA7 loss-of-function variants are associated with increased risk of Alzheimer's disease (AD). Using ABCA7 knockout human iPSC models generated with CRISPR/Cas9, we investigated the impacts of ABCA7 deficiency on neuronal metabolism and function. Lipidomics revealed that mitochondria-related phospholipids, such as phosphatidylglycerol and cardiolipin were reduced in the ABCA7-deficient iPSC-derived cortical organoids. Consistently, ABCA7 deficiency-induced alterations of mitochondrial morphology accompanied by reduced ATP synthase activity and exacerbated oxidative damage in the organoids. Furthermore, ABCA7-deficient iPSC-derived neurons showed compromised mitochondrial respiration and excess ROS generation, as well as enlarged mitochondrial morphology compared to the isogenic controls. ABCA7 deficiency also decreased spontaneous synaptic firing and network formation in iPSC-derived neurons, in which the effects were rescued by supplementation with phosphatidylglycerol or NAD+ precursor, nicotinamide mononucleotide. Importantly, effects of ABCA7 deficiency on mitochondria morphology and synapses were recapitulated in synaptosomes isolated from the brain of neuron-specific Abca7 knockout mice. Together, our results provide evidence that ABCA7 loss-of-function contributes to AD risk by modulating mitochondria lipid metabolism.
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Transportadoras de Casetes de Unión a ATP , Células Madre Pluripotentes Inducidas , Metabolismo de los Lípidos , Ratones Noqueados , Mitocondrias , Neuronas , Mitocondrias/metabolismo , Neuronas/metabolismo , Humanos , Animales , Metabolismo de los Lípidos/fisiología , Ratones , Células Madre Pluripotentes Inducidas/metabolismo , Transportadoras de Casetes de Unión a ATP/metabolismo , Transportadoras de Casetes de Unión a ATP/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Encéfalo/metabolismoRESUMEN
Microglial involvement in Alzheimer's disease (AD) pathology has emerged as a risk-determining pathogenic event. While apolipoprotein E (APOE) is known to modify AD risk, it remains unclear how microglial apoE impacts brain cognition and AD pathology. Here, using conditional mouse models expressing apoE isoforms in microglia and central nervous system-associated macrophages (CAMs), we demonstrate a cell-autonomous effect of apoE3-mediated microglial activation and function, which are negated by apoE4. Expression of apoE3 in microglia/CAMs improves cognitive function, increases microglia surrounding amyloid plaque and reduces amyloid pathology and associated toxicity, whereas apoE4 expression either compromises or has no effects on these outcomes by impairing lipid metabolism. Single-cell transcriptomic profiling reveals increased antigen presentation and interferon pathways upon apoE3 expression. In contrast, apoE4 expression downregulates complement and lysosomal pathways, and promotes stress-related responses. Moreover, in the presence of mouse endogenous apoE, microglial apoE4 exacerbates amyloid pathology. Finally, we observed a reduction in Lgals3-positive responsive microglia surrounding amyloid plaque and an increased accumulation of lipid droplets in APOE4 human brains and induced pluripotent stem cell-derived microglia. Our findings establish critical isoform-dependent effects of microglia/CAM-expressed apoE in brain function and the development of amyloid pathology, providing new insight into how apoE4 vastly increases AD risk.
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Enfermedad de Alzheimer , Ratones , Animales , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Microglía/metabolismo , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Placa Amiloide/metabolismo , Placa Amiloide/patología , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Encéfalo , Homeostasis , Ratones TransgénicosRESUMEN
The PINK1-PRKN pathway mediates a critical quality control to maintain mitochondrial health and function. Together the kinase-ligase pair identifies and decorate damaged mitochondria with phosphorylated ubiquitin (p-S65-Ub). This selective label serves as the mitophagy tag and facilitates their degradation via autophagy-lysosome system. While complete loss of PINK1 or PRKN function causes early-onset Parkinson disease, much broader mitophagy impairments are emerging across neurodegenerative disorders. We previously found age- and disease-dependent accumulation of p-S65-Ub signal in the hippocampus of autopsy brains with Lewy body disease (LBD). However, the contribution of genetic variation to mitochondrial damage and p-S65-Ub levels remains unknown in LBD cases. To identify novel regulators of PINK1-PRKN mitophagy in LBD, we performed an unbiased genome-wide association study of hippocampal p-S65-Ub level with 1,012 autopsy confirmed LBD samples. Using an established, mostly automated workflow, hippocampal sections were immunostained for p-S65-Ub, scanned, and quantified with unbiased algorithms. Functional validation of the significant hit was performed in animal model and human induced pluripotent stem cells (hiPSCs). We identified a strong association with p-S65-Ub for APOE4 (rs429358; ß : 0.50, 95% CI: 0.41 to 0.69; p =8.67x10 -25 ) and a genome-wide significant association for ZMIZ1 (rs6480922; ß : -0.33, 95% CI: -0.45 to -0.22; p =1.42x10 -8 ). The increased p-S65-Ub levels in APOE4 -carrier may be mediated by both co-pathology-dependent and -independent mechanisms, which was confirmed in Apoe-targeted replacement mice and hiPSC-derived astrocytes. Intriguingly, ZMIZ1 rs6480922 also significantly associated with increased brain weight and reduced neuropathological burden indicating a potential role as a resilience factor. Our findings nominate novel mitophagy regulators in LBD brain ( ZMIZ1 locus) and highlight a strong association of APOE4 with mitophagy alteration. With APOE4 being the strongest known risk factor for clinical Alzheimer's disease and dementia with Lewy bodies, our findings suggest a common mechanistic link underscoring the importance of mitochondrial quality control.
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BACKGROUND: The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer's disease (AD); however, how it modulates brain homeostasis is not clear. The apoE protein is a major lipid carrier in the brain transporting lipids such as cholesterol among different brain cell types. METHODS: We generated three-dimensional (3-D) cerebral organoids from human parental iPSC lines and its isogenic APOE-deficient (APOE-/-) iPSC line. To elucidate the cell-type-specific effects of APOE deficiency in the cerebral organoids, we performed scRNA-seq in the parental and APOE-/- cerebral organoids at Day 90. RESULTS: We show that APOE deficiency in human iPSC-derived cerebral organoids impacts brain lipid homeostasis by modulating multiple cellular and molecular pathways. Molecular profiling through single-cell RNA sequencing revealed that APOE deficiency leads to changes in cellular composition of isogenic cerebral organoids likely by modulating the eukaryotic initiation factor 2 (EIF2) signaling pathway as these events were alleviated by the treatment of an integrated stress response inhibitor (ISRIB). APOE deletion also leads to activation of the Wnt/ß-catenin signaling pathway with concomitant decrease of secreted frizzled-related protein 1 (SFRP1) expression in glia cells. Importantly, the critical role of apoE in cell-type-specific lipid homeostasis was observed upon APOE deletion in cerebral organoids with a specific upregulation of cholesterol biosynthesis in excitatory neurons and excessive lipid accumulation in astrocytes. Relevant to human AD, APOE4 cerebral organoids show altered neurogenesis and cholesterol metabolism compared to those with APOE3. CONCLUSIONS: Our work demonstrates critical roles of apoE in brain homeostasis and offers critical insights into the APOE4-related pathogenic mechanisms.
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Apolipoproteínas E , Cerebro , Células Madre Pluripotentes Inducidas , Humanos , Apolipoproteína E4 , Apolipoproteínas E/genética , Diferenciación Celular , Organoides , Cerebro/metabolismoRESUMEN
The prevalence of Alzheimer's disease is greater in women, but the underlying mechanisms remain to be elucidated. We herein demonstrated that α-secretase ADAM10 was downregulated and ADAM10 inhibitor sFRP1 was upregulated in 5xFAD mice. While there were no sex effects on ADAM10 protein and sFRP1 mRNA levels, female 5xFAD and age-matched non-transgenic mice exhibited higher levels of sFRP1 protein than corresponding male mice. Importantly, female 5xFAD mice accumulated more Aß than males, and sFRP1 protein levels were positively associated with Aß42 levels in 5xFAD mice. Our study suggests that sFRP1 is associated with amyloid pathology in a sex-dependent manner.
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Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Animales , Femenino , Masculino , Ratones , Proteína ADAM10/genética , Proteína ADAM10/metabolismo , Enfermedad de Alzheimer/patología , Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Proteínas Amiloidogénicas/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Ratones Transgénicos , Regulación hacia ArribaRESUMEN
Over the past decade, compelling genetic evidence has highlighted the crucial role of microglial dysregulation in the development of Alzheimer's disease (AD). As resident immune cells in the brain, microglia undergo dystrophy and senescence during the chronic progression of AD. To explore the potential therapeutic benefits of replenishing the brain with new microglia in AD, we utilized the CSF1R inhibitor PLX3397 to deplete existing microglia and induce repopulation after inhibitor withdrawal in 5xFAD transgenic mice. Our findings revealed the remarkable benefits of microglial repopulation in ameliorating AD-associated cognitive deficits, accompanied by a notable elevation in synaptic proteins and an enhancement of hippocampal long-term potentiation (LTP). Additionally, we observed the profound restoration of microglial morphology and synaptic engulfment following their self-renewal. The impact of microglial repopulation on amyloid pathology is dependent on the duration of repopulation. Transcriptome analysis revealed a high resemblance between the gene expression profiles of repopulated microglia from 5xFAD mice and those of microglia from WT mice. Importantly, the dysregulated neurotrophic signaling pathway and hippocampal neurogenesis in the AD brain are restored following microglial replenishment. Lastly, we demonstrated that the repopulation restores the expression of brain-derived neurotrophic factor (BDNF) in microglia, thereby contributing to synaptic plasticity. In conclusion, our findings provide compelling evidence to support the notion that microglial self-renewal confers substantial benefits to the AD brain by restoring the BDNF neurotrophic signaling pathway. Thus, targeted microglial repopulation emerges as a highly promising and novel therapeutic strategy for alleviating cognitive impairment in AD.
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Enfermedad de Alzheimer , Ratones , Animales , Enfermedad de Alzheimer/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Microglía/metabolismo , Ratones Transgénicos , Transducción de Señal , Cognición , Modelos Animales de EnfermedadRESUMEN
Vascular cognitive impairment and dementia (VCID) is commonly caused by vascular injuries in cerebral large and small vessels and is a key driver of age-related cognitive decline. Severe VCID includes post-stroke dementia, subcortical ischemic vascular dementia, multi-infarct dementia, and mixed dementia. While VCID is acknowledged as the second most common form of dementia after Alzheimer's disease (AD) accounting for 20% of dementia cases, VCID and AD frequently coexist. In VCID, cerebral small vessel disease (cSVD) often affects arterioles, capillaries, and venules, where arteriolosclerosis and cerebral amyloid angiopathy (CAA) are major pathologies. White matter hyperintensities, recent small subcortical infarcts, lacunes of presumed vascular origin, enlarged perivascular space, microbleeds, and brain atrophy are neuroimaging hallmarks of cSVD. The current primary approach to cSVD treatment is to control vascular risk factors such as hypertension, dyslipidemia, diabetes, and smoking. However, causal therapeutic strategies have not been established partly due to the heterogeneous pathogenesis of cSVD. In this review, we summarize the pathophysiology of cSVD and discuss the probable etiological pathways by focusing on hypoperfusion/hypoxia, blood-brain barriers (BBB) dysregulation, brain fluid drainage disturbances, and vascular inflammation to define potential diagnostic and therapeutic targets for cSVD.
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Enfermedad de Alzheimer , Enfermedades de los Pequeños Vasos Cerebrales , Demencia Vascular , Humanos , Causalidad , Factores de Riesgo , Enfermedades de los Pequeños Vasos Cerebrales/complicacionesRESUMEN
Triggering receptor expressed on myeloid cells 2 (TREM2) is strongly linked to Alzheimer's disease (AD) risk, but its functions are not fully understood. Here, we found that TREM2 specifically attenuated the activation of classical complement cascade via high-affinity binding to its initiator C1q. In the human AD brains, the formation of TREM2-C1q complexes was detected, and the increased density of the complexes was associated with lower deposition of C3 but higher amounts of synaptic proteins. In mice expressing mutant human tau, Trem2 haploinsufficiency increased complement-mediated microglial engulfment of synapses and accelerated synaptic loss. Administration of a 41-amino-acid TREM2 peptide, which we identified to be responsible for TREM2 binding to C1q, rescued synaptic impairments in AD mouse models. We thus demonstrate a critical role for microglial TREM2 in restricting complement-mediated synaptic elimination during neurodegeneration, providing mechanistic insights into the protective roles of TREM2 against AD pathogenesis.
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Enfermedad de Alzheimer , Complemento C1q , Ratones , Animales , Humanos , Complemento C1q/genética , Complemento C1q/metabolismo , Encéfalo/metabolismo , Sinapsis/metabolismo , Activación de Complemento , Microglía/metabolismo , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismoRESUMEN
BACKGROUND: While obesity in midlife is a risk factor for dementia, several studies suggested that obesity also protected against dementia, hence so-called obesity paradox. The current study aims to address the relationship between apolipoprotein E (APOE) genotype and obesity in dementia. METHODS: Clinical and neuropathological records of the National Alzheimer's Coordinating Center (NACC) in the USA, which longitudinally followed approximately 20 000 subjects with different cognitive statues, APOE genotype and obesity states, were reviewed. RESULTS: Obesity was associated with cognitive decline in early elderly cognitively normal individuals without APOE4, especially those with APOE2. Neuropathological analyses adjusted for dementia status showed that APOE2 carriers tended to have more microinfarcts and haemorrhages due to obesity. On the other hand, obesity was associated with a lower frequency of dementia and less cognitive impairment in individuals with mild cognitive impairment or dementia. Such trends were particularly strong in APOE4 carriers. Obesity was associated with fewer Alzheimer's pathologies in individuals with dementia. CONCLUSIONS: Obesity may accelerate cognitive decline in middle to early elderly cognitive normal individuals without APOE4 likely by provoking vascular impairments. On the other hand, obesity may ease cognitive impairment in both individuals with dementia and individuals at the predementia stage, especially those with APOE4, through protecting against Alzheimer's pathologies. These results support that APOE genotype modifies the obesity paradox in dementia.
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Enfermedad de Alzheimer , Anciano , Humanos , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/psicología , Apolipoproteína E2/genética , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Genotipo , Obesidad/complicaciones , Obesidad/genética , Paradoja de la ObesidadRESUMEN
Alpha-synuclein (αsyn) aggregates are pathological features of several neurodegenerative conditions including Parkinson disease (PD), dementia with Lewy bodies, and multiple system atrophy (MSA). Accumulating evidence suggests that mitochondrial dysfunction and impairments of the autophagic-lysosomal system can contribute to the deposition of αsyn, which in turn may interfere with health and function of these organelles in a potentially vicious cycle. Here we investigated a potential convergence of αsyn with the PINK1-PRKN-mediated mitochondrial autophagy pathway in cell models, αsyn transgenic mice, and human autopsy brain. PINK1 and PRKN identify and selectively label damaged mitochondria with phosphorylated ubiquitin (pS65-Ub) to mark them for degradation (mitophagy). We found that disease-causing multiplications of αsyn resulted in accumulation of the ubiquitin ligase PRKN in cells. This effect could be normalized by starvation-induced autophagy activation and by CRISPR/Cas9-mediated αsyn knockout. Upon acute mitochondrial damage, the increased levels of PRKN protein contributed to an enhanced pS65-Ub response. We further confirmed increased pS65-Ub-immunopositive signals in mouse brain with αsyn overexpression and in postmortem human disease brain. Of note, increased pS65-Ub was associated with neuronal Lewy body-type αsyn pathology, but not glial cytoplasmic inclusions of αsyn as seen in MSA. While our results add another layer of complexity to the crosstalk between αsyn and the PINK1-PRKN pathway, distinct mechanisms may underlie in cells and brain tissue despite similar outcomes. Notwithstanding, our finding suggests that pS65-Ub may be useful as a biomarker to discriminate different synucleinopathies and may serve as a potential therapeutic target for Lewy body disease.
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Enfermedad de Parkinson , alfa-Sinucleína , Animales , Humanos , Ratones , alfa-Sinucleína/metabolismo , Ratones Transgénicos , Mitofagia , Enfermedad de Parkinson/metabolismo , Proteínas Quinasas/metabolismo , Proteínas Quinasas/farmacología , Ubiquitina/metabolismo , Ubiquitina/farmacología , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Progression of Alzheimer's disease (AD) entails deterioration or aberrant function of multiple brain cell types, eventually leading to neurodegeneration and cognitive decline. Defining how complex cell-cell interactions become dysregulated in AD requires novel human cell-based in vitro platforms that could recapitulate the intricate cytoarchitecture and cell diversity of the human brain. Brain organoids (BOs) are 3D self-organizing tissues that partially resemble the human brain architecture and can recapitulate AD-relevant pathology. In this review, we highlight the versatile applications of different types of BOs to model AD pathogenesis, including amyloid-ß and tau aggregation, neuroinflammation, myelin breakdown, vascular dysfunction, and other phenotypes, as well as to accelerate therapeutic development for AD.