RESUMO
BACKGROUND: Variants in APOE and PSEN1 (encoding apolipoprotein E and presenilin 1, respectively) alter the risk of Alzheimer's disease. We previously reported a delay of cognitive impairment in a person with autosomal dominant Alzheimer's disease caused by the PSEN1 E280A variant who also had two copies of the apolipoprotein E3 Christchurch variant (APOE3 Ch). Heterozygosity for the APOE3 Ch variant may influence the age at which the onset of cognitive impairment occurs. We assessed this hypothesis in a population in which the PSEN1 E280A variant is prevalent. METHODS: We analyzed data from 27 participants with one copy of the APOE3 Ch variant among 1077 carriers of the PSEN1 E280A variant in a kindred from Antioquia, Colombia, to estimate the age at the onset of cognitive impairment and dementia in this group as compared with persons without the APOE3 Ch variant. Two participants underwent brain imaging, and autopsy was performed in four participants. RESULTS: Among carriers of PSEN1 E280A who were heterozygous for the APOE3 Ch variant, the median age at the onset of cognitive impairment was 52 years (95% confidence interval [CI], 51 to 58), in contrast to a matched group of PSEN1 E280A carriers without the APOE3 Ch variant, among whom the median age at the onset was 47 years (95% CI, 47 to 49). In two participants with the APOE3 Ch and PSEN1 E280A variants who underwent brain imaging, 18F-fluorodeoxyglucose positron-emission tomographic (PET) imaging showed relatively preserved metabolic activity in areas typically involved in Alzheimer's disease. In one of these participants, who underwent 18F-flortaucipir PET imaging, tau findings were limited as compared with persons with PSEN1 E280A in whom cognitive impairment occurred at the typical age in this kindred. Four studies of autopsy material obtained from persons with the APOE3 Ch and PSEN1 E280A variants showed fewer vascular amyloid pathologic features than were seen in material obtained from persons who had the PSEN1 E280A variant but not the APOE3 Ch variant. CONCLUSIONS: Clinical data supported a delayed onset of cognitive impairment in persons who were heterozygous for the APOE3 Ch variant in a kindred with a high prevalence of autosomal dominant Alzheimer's disease. (Funded by Good Ventures and others.).
Assuntos
Doença de Alzheimer , Apolipoproteína E3 , Presenilina-1 , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Idade de Início , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Apolipoproteína E3/genética , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Colômbia , Família , Genes Dominantes , Heterozigoto , Tomografia por Emissão de Pósitrons , Presenilina-1/genética , Estudos RetrospectivosRESUMO
Highly penetrant autosomal dominant Alzheimer's disease (ADAD) comprises a distinct disease entity as compared to the far more prevalent form of AD in which common variants collectively contribute to risk. The downstream pathways that distinguish these AD forms in specific cell types have not been deeply explored. We compared single-nucleus transcriptomes among a set of 27 cases divided among PSEN1-E280A ADAD carriers, sporadic AD, and controls. Autophagy genes and chaperones clearly defined the PSEN1-E280A cases compared to sporadic AD. Spatial transcriptomics validated the activation of chaperone-mediated autophagy genes in PSEN1-E280A. The PSEN1-E280A case in which much of the brain was spared neurofibrillary pathology and harbored a homozygous APOE3-Christchurch variant revealed possible explanations for protection from AD pathology including overexpression of LRP1 in astrocytes, increased expression of FKBP1B, and decreased PSEN1 expression in neurons. The unique cellular responses in ADAD and sporadic AD require consideration when designing clinical trials.
Assuntos
Doença de Alzheimer , Presenilina-1 , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Humanos , Presenilina-1/genética , Masculino , Feminino , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Análise de Sequência de RNA/métodos , Autofagia/genética , Transcriptoma , Idoso , Neurônios/metabolismo , Neurônios/patologia , Pessoa de Meia-Idade , Astrócitos/metabolismo , Astrócitos/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Proteínas de Ligação a Tacrolimo/genética , Idoso de 80 Anos ou mais , Análise de Célula ÚnicaRESUMO
We characterized the world's second case with ascertained extreme resilience to autosomal dominant Alzheimer's disease (ADAD). Side-by-side comparisons of this male case and the previously reported female case with ADAD homozygote for the APOE3 Christchurch (APOECh) variant allowed us to discern common features. The male remained cognitively intact until 67 years of age despite carrying a PSEN1-E280A mutation. Like the APOECh carrier, he had extremely elevated amyloid plaque burden and limited entorhinal Tau tangle burden. He did not carry the APOECh variant but was heterozygous for a rare variant in RELN (H3447R, termed COLBOS after the Colombia-Boston biomarker research study), a ligand that like apolipoprotein E binds to the VLDLr and APOEr2 receptors. RELN-COLBOS is a gain-of-function variant showing stronger ability to activate its canonical protein target Dab1 and reduce human Tau phosphorylation in a knockin mouse. A genetic variant in a case protected from ADAD suggests a role for RELN signaling in resilience to dementia.
Assuntos
Doença de Alzheimer , Animais , Feminino , Humanos , Masculino , Camundongos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Heterozigoto , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: Depression is associated with Alzheimer's disease (AD). OBJECTIVE: To evaluate the association between depressive symptoms and age of onset of cognitive decline in autosomal dominant AD, and to determine possible factors associated to early depressive symptoms in this population. METHODS: We conducted a retrospective study to identify depressive symptoms among 190 presenilin 1 (PSEN1) E280A mutation carriers, subjected to comprehensive clinical evaluations in up to a 20-year longitudinal follow-up. We controlled for the following potential confounders: APOE, sex, hypothyroidism, education, marital status, residence, tobacco, alcohol, and drug abuse. RESULTS: PSEN1 E280A carriers with depressive symptoms before mild cognitive impairment (MCI) develop dementia faster than E280A carriers without depressive symptoms (Hazard Ratio, HRâ=â1.95; 95% CI, 1.15-3.31). Not having a stable partner accelerated the onset of MCI (HRâ=â1.60; 95 % CI, 1.03-2.47) and dementia (HRâ=â1.68; 95 % CI, 1.09-2.60). E280A carriers with controlled hypothyroidism had later age of onset of depressive symptoms (HRâ=â0.48; 95 % CI, 0.25-0.92), dementia (HRâ=â0.43; 95 % CI, 0.21-0.84), and death (HRâ=â0.35; 95 % CI, 0.13-0.95). APOEÉ2 significantly affected AD progression in all stages. APOE polymorphisms were not associate to depressive symptoms. Women had a higher frequency and developed earlier depressive symptoms than men throughout the illness (HRâ=â1.63; 95 % CI, 1.14-2.32). CONCLUSION: Depressive symptoms accelerated progress and faster cognitive decline of autosomal dominant AD. Not having a stable partner and factors associated with early depressive symptoms (e.g., in females and individuals with untreated hypothyroidism), could impact prognosis, burden, and costs.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Feminino , Humanos , Masculino , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Doença de Alzheimer/diagnóstico , Apolipoproteínas E/genética , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/diagnóstico , Depressão/epidemiologia , Depressão/genética , Progressão da Doença , Estudos RetrospectivosRESUMO
In response to brain insults, astrocytes become reactive, promoting protection and tissue repair. However, astroglial reactivity is typical of brain pathologies, including Alzheimer's disease (AD). Considering the heterogeneity of the reactive response, the role of astrocytes in the course of different forms of AD has been underestimated. Colombia has the largest human group known to have familial AD (FAD). This group carries the autosomal dominant and fully penetrant mutation E280A in PSEN1, which causes early-onset AD. Recently, our group identified an E280A carrier who did not develop FAD. The individual was homozygous for the Christchurch mutation R136S in APOE3 (APOEch). Remarkably, APOE is the main genetic risk factor for developing sporadic AD (SAD) and most of cerebral ApoE is produced by astroglia. Here, we characterized astrocyte properties related to reactivity, glutamate homeostasis, and structural integrity of the gliovascular unit (GVU), as factors that could underlie the pathogenesis or protection of AD. Specifically, through histological and 3D microscopy analyses of postmortem samples, we briefly describe the histopathology and cytoarchitecture of the frontal cortex of SAD, FAD, and APOEch, and demonstrate that, while astrodegeneration and vascular deterioration are prominent in SAD, FAD is characterized by hyperreactive-like glia, and APOEch displays the mildest astrocytic and vascular alterations despite having the highest burden of Aß. Notably, astroglial, gliovascular, and vascular disturbances, as well as brain cell death, correlate with the specific astrocytic phenotypes identified in each condition. This study provides new insights into the potential relevance of the gliovasculature in the development and protection of AD. To our knowledge, this is the first study assessing the components of the GVU in human samples of SAD, FAD, and APOEch.
Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/patologia , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Homozigoto , Mutação , Encéfalo/patologia , Peptídeos beta-Amiloides/metabolismoRESUMO
Alzheimer's disease pathology is characterized by ß-amyloid plaques and neurofibrillary tangles. Amyloid precursor protein is processed by ß and γ secretase, resulting in the production of ß-amyloid peptides with a length ranging from 38 to 43 amino acids. Presenilin 1 (PS1) is the catalytic unit of γ-secretase, and more than 200 PS1 pathogenic mutations have been identified as causative for Alzheimer's disease. A complete monocrystal structure of PS1 has not been determined so far due to the presence of two flexible domains. We have developed a complete structural model of PS1 using a computational approach with structure prediction software. Missing fragments Met1-Glut72 and Ser290-Glu375 were modeled and validated by their energetic and stereochemical characteristics. Then, with the complete structure of PS1, we defined that these fragments do not have a direct effect in the structure of the pore. Next, we used our hypothetical model for the analysis of the functional effects of PS1 mutations Ala246GLu, Leu248Pro, Leu248Arg, Leu250Val, Tyr256Ser, Ala260Val, and Val261Phe, localized in the catalytic pore. For this, we used a quantum mechanics/molecular mechanics (QM/MM) hybrid method, evaluating modifications in the topology, potential surface density, and electrostatic potential map of mutated PS1 proteins. We found that each mutation exerts changes resulting in structural modifications of the active site and in the shape of the pore. We suggest this as a valid approach for functional studies of PS1 in view of the possible impact in substrate processing and for the design of targeted therapeutic strategies.
Assuntos
Envelhecimento , Encéfalo/fisiologia , Plasticidade Neuronal , Envelhecimento Saudável , HumanosRESUMO
Presenilin 1 (PS1) mutations are the most common cause of early-onset familial Alzheimer's disease (EOFAD). They show a common phenotypic profile characterized by early age of onset, severe dementia and distinct neurodegeneration. The largest population of EOFAD carries the E280A mutation in PS1 and resides in Antioquia, Colombia, currently comprising around 5,000 individuals. Carriers start showing memory impairment in the third decade of life, followed by progressive impairment of language and other cognitive processes. They reach mild cognitive impairment around 45 and dementia around 50 years of age. There is some phenotypic variability among the carriers of this single PS1 mutation. Some patients present with epilepsy, verbal impairment, and cerebellar ataxia. Neuropathologically, PS1 E280A cases show pronounced brain atrophy, severe amyloid-ß pathology, distinct hyperphosphorylated tau-related pathology, and cerebellar damage. The earliest event identified by functional magnetic imaging resonance is hyperactivation within the right anterior hippocampus around 33 years of age. This well-studied population with a clear pre-clinical profile and wide phenotypic variability in age of onset and clinical presentation is ideally suited for clinical trials and to study molecular mechanisms of Alzheimer's disease.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/psicologia , Mutação/genética , Presenilina-1/genética , Adulto , Idade de Início , Idoso , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Encéfalo/patologia , Cognição/fisiologia , Colômbia/epidemiologia , Heterozigoto , Humanos , Pessoa de Meia-Idade , Mutação/fisiologia , Fenótipo , Presenilina-2/genéticaRESUMO
BACKGROUND: Mild cognitive impairment (MCI) and pre-MCI have been proposed as stages preceding Alzheimer's disease (AD) dementia. We assessed descendants of individuals with a mutation in presenilin 1 (PSEN1) that causes familial AD, with the aim of identifying distinct stages of clinical progression to AD dementia. METHODS: We retrospectively studied a cohort of descendants of carriers of the PSEN1 E280A mutation. Pre-dementia cognitive impairment was defined by a score 2 SD away from normal values in objective cognitive tests, and was subdivided as follows: asymptomatic pre-MCI was defined by an absence of memory complaints and no effect on activities of daily living; symptomatic pre-MCI was defined by a score on the subjective memory complaints checklist higher than the mean and no effect on activities of daily living; and MCI was defined by a score on the subjective memory complaints checklist higher than the mean, with no effect on basic activities of daily living and little or no effect on complex daily activities. Dementia was defined according to the diagnostic and statistical manual of mental disorders, fourth edition. Reference mean scores were those of participants who did not carry the PSEN1 E280A mutation. We used the Turnbull survival analysis method to identify ages at onset of each stage of the disease. We measured the time from birth until onset of the three pre-dementia stages, dementia, and death, and assessed decline in cognitive domains for each stage. FINDINGS: Follow-up was from Jan 1, 1995, to Jan 27, 2010. 1784 patients were initially identified, 449 of whom were PSEN1 E280A carriers who had complete clinical follow-up. Median age at onset was 35 years (95% CI 30-36) for asymptomatic pre-MCI, 38 years (37-40) for symptomatic pre-MCI, 44 years (43-45) for MCI, and 49 years (49-50) for dementia. The median age at death was 59 years (95% CI 58-61). The median time of progression from asymptomatic to symptomatic pre-MCI was 4 years (95% CI 2-8), from symptomatic pre-MCI to MCI was 6 years (4-7), from MCI to dementia was 5 years (4-6), and from dementia to death was 10 years (9-12). The cognitive profile was predominantly amnestic and was associated with multiple domains. Affected domains showed variability in initial stages, with some transient recovery in symptomatic pre-MCI followed by continuous decline. INTERPRETATION: Clinical deterioration can be detected as measurable cognitive impairment around two decades before dementia onset in PSEN1 E280A carriers. Onset and progression of pre-dementia stages should be considered in the investigation and use of therapeutic interventions for familial AD. FUNDING: Departamento Administrativo de Ciencia, Tecnología e Innovación, COLCIENCIAS, Republic of Colombia.
Assuntos
Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Marcadores Genéticos/genética , Heterozigoto , Mutação/genética , Adulto , Idade de Início , Doença de Alzheimer/diagnóstico , Estudos de Coortes , Demência/diagnóstico , Demência/epidemiologia , Demência/genética , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Presenilina-1 , Estudos RetrospectivosRESUMO
El DHEAS es un neuroesteroide con efecto neuromodulador de la transmisión sináptica y en la neuroprotección, sin embargo las vías moleculares a través de las cuales se inducen estos cambiosno están completamente claras. Como varios de los neuroesteroides actúan a través de los recetores ionotrópicos de glutamato, se evaluó el efecto del DHEAS en las subunidades GluR2 y GluR3 del receptor AMPA para esclarecer sus efectos. Con este fin se administró DHEAS o una sustancia control durante 7 días a ratones C57/BL6. La expresión de las subunidades se evaluó por Westernblotting.Los resultados presentados muestran que la administración prolongada de 40mg/kg/día de DHEAS a ratones C57/BL6 produce un incremento en los niveles de proteína de las subunidades GluR2/3 yGluR2 del receptor AMPA en el hipocampo. Dado el papel específico que juega la subunidad GluR2 del receptor AMPA en el control de la entrada de calcio durante los procesos de muerte celular y de plasticidad sináptica, este hallazgo contribuye al estudio de los neuroesteroides como una estrategia terapéutica relevante en enfermedades neurodegenerativas y eventos cerebrovasculares.
Dehydroepiandrosterone sulfate (DHEA-S) is a neurosteroid that has effects such as neuromodulator of synaptic transmission and neuroprotection. The specific signaling pathways for these effects are not elucidated yet. Given that, some neurosteroids act through the activation of ionotropic glutamate receptors, therefore the effect of DHEA-S on the subunits GluR2 and GluR3of the AMPA receptor was evaluated. Either DHEA-S or a control substance was administered to C57/BL6 mice. Subunit expression of the AMPA receptor was analyzed by Western blotting. Results show that long-term DHEA-S administration toC57/BL6 mice, increases the protein levels of the subunits GluR2 and GluR2/3 of the AMPA receptors located in the hippocampus. Due to the role of AMPA receptor, specifically GluR2subunit in the regulation of intracellular calcium levels, cellular apoptosis, and synaptic plasticity, the study of neurosteroids as a therapeutic strategy in neurodegenerative diseases and cerebrovascular events is very relevant.
Assuntos
Camundongos , Hipocampo , Camundongos , Receptores de AMPA , Transmissão SinápticaRESUMO
We previously identified in two families with early onset Parkinson's Disease (PD) from the isolated population of Antioquia (Colombia), a parkin Cys212Tyr substitution caused by a G736A mutation. This mutation was subsequently observed in a Spanish family, suggesting that it could have been taken to Antioquia by Spanish immigrants. Here we screened for the G736A mutation in additional Antioquian early onset PD cases and used haplotype analysis to investigate the relationship between Spanish and Antioquian G736A chromosomes. We confirmed the occurrence of an extensive founder effect in Antioquia. Thirteen individuals (10 homozygotes) from seven nuclear families were identified with the G736A mutation. Genealogical investigations demonstrated the existence of shared ancestors between six of these families four to five generations ago and no evidence of Spanish ancestry during this period. A second parkin mutation (a duplication of exon 3), was detected in the three G736A heterozygote carriers. Haplotype data exclude a recent common ancestry between the Spanish and Antioquian patients studied here and is consistent with the introduction of the G736A mutation in Antioquia during early colonial times (about 16 generations ago).