JOSE MARCELO FARFEL
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Ortopediae Traumatologia, Faculdade de Medicina - Docente
LIM/22 - Laboratório de Patolologia Cardiovascular, Hospital das Clínicas, Faculdade de Medicina
LIM/22 - Laboratório de Patolologia Cardiovascular, Hospital das Clínicas, Faculdade de Medicina
3 resultados
Resultados de Busca
Agora exibindo 1 - 3 de 3
- Association of APOE with tau-tangle pathology with and without beta-amyloid(2016) FARFEL, Jose M.; YU, Lei; JAGER, Philip L. De; SCHNEIDER, Julie A.; BENNETT, David A.This study tested the hypothesis that the association of apolipoprotein E (APOE) with paired helical filament tau (PHF-tau) tangle pathology differs in brains with and without beta-amyloid. Participants were 1056 autopsied individuals from 2 clinical-pathologic cohort studies of aging and Alzheimer's disease (AD), the Religious Orders Study, and the Rush Memory and Aging Project. Neuropathologic measures were obtained using immunohistochemistry targeting beta-amyloid and PHF-tau tangles in 8 brain regions. Linear regression was used to compare the relation of APOE epsilon 4 and epsilon 2 to PHF-tau-tangle density in persons with beta-amyloid relative to persons without beta-amyloid. We found an interaction between APOE epsilon 4 carriers and presence of beta-amyloid (beta = -0.968, p = 0.013) such that the association of APOE epsilon 4 with PHF-tau tangles was much stronger in brains with beta-amyloid. Stratified analysis shows that the association of APOE epsilon 4 with PHF-tau tangles was considerably stronger among those with beta-amyloid (beta = 0.757, p = 1.1 x 10(-15)) compared to those without beta-amyloid which was not significant (beta = -0.201, p = 0.424). Separately, APOE epsilon 2 was associated with fewer tangles in brains with beta-amyloid (beta = -0.425, p = 7.6 x 10(-4)) compared to those without beta-amyloid which was not significant (beta = -0.102, p = 0.506). Thus, the presence of APOE epsilon 4 and epsilon 2 alleles was not associated with PHF-tau tangles in the absence of beta-amyloid. The data provide additional evidence that PHF-tau tangles in the absence of beta-amyloid may reflect a pathologic process distinct from Alzheimer's disease.
- Lower mitochondrial DNA content but not increased mutagenesis associates with decreased base excision repair activity in brains of AD subjects(2019) SOLTYS, Daniela T.; PEREIRA, Carolina P. M.; ROWIES, Fernanda T.; FARFEL, Jose M.; GRINBERG, Lea T.; SUEMOTO, Claudia K.; LEITE, Renata E. P.; RODRIGUEZ, Roberta D.; ERICSON, Nolan G.; BIELAS, Jason H.; SOUZA-PINTO, Nadja C.Accumulation of oxidative mitochondrial DNA (mtDNA) damage and impaired base excision repair (BER) in brains have been associated with Alzheimer's disease (AD). However, it is still not clear how these affect mtDNA stability, as reported levels of mtDNA mutations in AD are conflicting. Thus, we investigated whether alterations in BER correlate with mtDNA instability in AD using postmortem brain samples from cognitively normal AD subjects and individuals who show neuropathological features of AD, but remained cognitively normal (high-pathology control). To date, no data on DNA repair and mtDNA stability are available for these individuals. BER activities, mtDNA mutations, and mtDNA copy number were measured in the nuclear and mitochondrial extracts. Significantly lower uracil DNA glycosylase activity was detected in nuclear and mitochondrial extracts from AD subjects, while apurinic/ apyrimidinic endonuclease activity was similar in all groups. Although mtDNA mutation frequency was similar in all groups, mtDNA copy number was significantly decreased in the temporal cortex of AD brains but not of high-pathology control subjects. Our results show that lower mitochondrial uracil DNA glycosylase activity does not result in increased mutagenesis, but rather in depletion of mtDNA in earlyaffected brain regions during AD development.
- APOE and cerebral amyloid angiopathy in community-dwelling older persons(2015) YU, Lei; BOYLE, Patricia A.; NAG, Sukriti; LEURGANS, Sue; BUCHMAN, Aron S.; WILSON, Robert S.; ARVANITAKIS, Zoe; FARFEL, Jose M.; JAGER, Philip L. De; BENNETT, David A.; SCHNEIDER, Julie A.Both cerebral amyloid angiopathy and Alzheimer's disease pathology involve abnormal beta-amyloid processing. We aim to elucidate the relationship of the apolipoprotein E (APOE) genotypes with amyloid angiopathy in the presence of variable amounts of Alzheimer's pathology. Data came from 1062 autopsied subjects from 2 community-based studies of aging. Common neuropathologies including Alzheimer's disease and amyloid angiopathy were assessed using uniform methods. APOE was genotyped by sequencing the 2 polymorphisms in codons 112 and 158 of exon 4. We examined the associations of APOE with amyloid angiopathy using ordinal logistic regression analyses, controlling for demographics and subsequently Alzheimer's and other common pathologies. Moderate to severe amyloid angiopathy was identified in 35.2% (n = 374) of the subjects; 15.3% (n = 162) of the subjects were APOE epsilon 2 carriers; and 26.1% (n = 277) epsilon 4 carriers. Adjusting for demographics, the presence of epsilon 4 allele, but not epsilon 2, was associated with more severe amyloid angiopathy. After further adjustment for Alzheimer's pathology, both epsilon 2 (odds ratio 1.707, 95% confidence interval 1.236-2.358, p = 0.001) and epsilon 4 (odds ratio 2.284, 95% confidence interval 1.730-3.014, p < 0.001) were independently associated with amyloid angiopathy. The results were confirmed by path analysis. Furthermore, APOE epsilon 4 carriers, but not epsilon 2 carriers, were more likely to have capillary amyloid angiopathy. Accounting for capillary involvement did not alter the APOE associations with amyloid angiopathy. We conclude that both APOE epsilon 2 and epsilon 4 alleles are associated with more severe cerebral amyloid angiopathy, and the direct effect of epsilon 2 is masked by the allele's negative association with comorbid Alzheimer's pathology. APOE epsilon 4, but not epsilon 2, is associated with capillary amyloid angiopathy.