Dataset Information

Association of APOE with tau-tangle pathology with and without ?-amyloid.

ABSTRACT: 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 ?-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 ?-amyloid and PHF-tau tangles in 8 brain regions. Linear regression was used to compare the relation of APOE ?4 and ?2 to PHF-tau-tangle density in persons with ?-amyloid relative to persons without ?-amyloid. We found an interaction between APOE ?4 carriers and presence of ?-amyloid (? = -0.968, p = 0.013) such that the association of APOE ?4 with PHF-tau tangles was much stronger in brains with ?-amyloid. Stratified analysis shows that the association of APOE ?4 with PHF-tau tangles was considerably stronger among those with ?-amyloid (? = 0.757, p = 1.1 × 10(-15)) compared to those without ?-amyloid which was not significant (? = -0.201, p = 0.424). Separately, APOE ?2 was associated with fewer tangles in brains with ?-amyloid (? = -0.425, p = 7.6 × 10(-4)) compared to those without ?-amyloid which was not significant (? = -0.102, p = 0.506). Thus, the presence of APOE ?4 and ?2 alleles was not associated with PHF-tau tangles in the absence of ?-amyloid. The data provide additional evidence that PHF-tau tangles in the absence of ?-amyloid may reflect a pathologic process distinct from Alzheimer's disease.

SUBMITTER: Farfel JM

PROVIDER: S-EPMC4716785 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Association of APOE with tau-tangle pathology with and without β-amyloid.

Farfel Jose M JM Yu Lei L De Jager Philip L PL Schneider Julie A JA Bennett David A DA

Neurobiology of aging 20150928

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 β-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 β-amyloid and PHF-tau tangles in 8 brain reg ...[more]

PMID: 26481403

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Project description:Tau is an axonal microtubule-binding protein. Tau pathology in brain and increased tau concentration in the cerebrospinal fluid (CSF) are hallmarks of Alzheimer's disease (AD). Most of tau in CSF is present as fragments. We immunoprecipitated tau from CSF and identified several endogenous peptides ending at amino acid (aa) 123 or 224 using high-resolution mass spectrometry. We raised neo-epitope-specific antibodies against tau fragments specifically ending at aa 123 and 224, respectively. With these antibodies, we performed immunohistochemistry on brain tissue and designed immunoassays measuring N-123, N-224, and x-224 tau. Immunoassays were applied to soluble brain fractions from pathologically confirmed subjects (81 AD patients, 33 controls), CSF from three cross-sectional and two longitudinal cohorts (a total of 133 AD, 38 MCI, 20 MCI-AD, 31 PSP, 15 CBS patients, and 91 controls), and neuronally- and peripherally-derived extracellular vesicles (NDEVs and PDEVs, respectively) in serum from four AD patients and four controls. Anti-tau 224 antibody stained neurofibrillary tangles and neuropil threads, while anti-tau 123 only showed weak cytoplasmic staining in AD. N-224 tau was lower in the AD soluble brain fraction compared to controls, while N-123 tau showed similar levels. N-224 tau was higher in AD compared to controls in all CSF cohorts (p?<?0.001), but not N-123 tau. Decrease in cognitive performance and conversion from MCI to AD were associated with increased baseline CSF levels of N-224 tau (p?<?0.0001). N-224 tau concentrations in PSP and CBS were significantly lower than in AD (p?<?0.0001) and did not correlate to t-tau and p-tau. In a longitudinal cohort, CSF N-224 tau levels were stable over 6 months, with no significant effect of treatment with AChE inhibitors. N-224 tau was present in NDEVs, while N-123 tau showed comparable concentrations in both vesicle types. We suggest that N-123 tau is produced both in CNS and PNS and represents a general marker of tau metabolism, while N-224 tau is neuron-specific, present in the tangles, secreted in CSF, and upregulated in AD, suggesting a link between tau cleavage and propagation, tangle pathology, and cognitive decline.

Dataset Information

Association of APOE with tau-tangle pathology with and without ?-amyloid.

Publications

Association of APOE with tau-tangle pathology with and without β-amyloid.

Similar Datasets

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