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14-3-3 proteins play roles in phosphorylation of tau proteins in neurofibrillary tangles (NFT) in Alzheimer's disease (AD). Tau is phosphorylated at serine (pSer) and threonine (pThr) in NFT, and NFT morphology varies according to phosphorylated sites and tau isoform. The roles of 14-3-3 proteins in NFT morphology remain unknown. This study was performed to examine the relationships between 14 and 3-3 proteins and tau phosphorylation of NFT. NFT were labeled with Gallyas impregnation, tau and 14-3-3 immunohistochemistry in paraffin-embedded hippocampal sections from seven AD and three control brains. Anti-tau antisera included monoclonal antisera that recognize pSer262 (pSer262), pSer422 (pSer422), pSer202/pThr205 (AT8), Thr231 (AT180), three-repeat (RD3) and four-repeat (RD4) tau isoform. Anti-14-3-3 protein isoform antisera included polyclonal antisera to beta, gamma, zeta, epsilon, tau, mu and sigma isoforms and monoclonal antiserum to beta antiserum (H8-beta). NFT density was obtained by counting labeled NFT in cornu ammonis (CA) 1–CA4, subiculum and entorhinal cortex. H8-beta and zeta isoforms were strongly expressed in NFT. Regional densities of NFT positive for pSer262, AT8, AT180, and Gallyas impregnation were similar to RD3-positive NFT density with high densities in CA1 and entorhinal cortex. NFT positive for pSer422 showed a similar regional distribution to RD4-positive NFT with high NFT density in CA2–CA4. H8-beta-positive NFT showed a similar regional distribution to RD3-positive NFT. In contrast, zeta isoform-positive NFT showed no specific distribution. In conclusion, H8-beta isoform is associated with development of 3-repeats NFT but a role of 14-3-3 zeta isoform in NFT could not be specified. [ABSTRACT FROM AUTHOR]

Abstract: This study reports correlation of the hippocampal neurofibrillary tangles (NFT) density with beta-amyloid (Aβ) precursor protein (APP) 717 mutation, presenilin (PS)-1 mutation and apolipoprotein E (Apo-E) e4 alleles (E4), being graded as 3 forms (no-E4, one-E4 and two-E4) in autopsied brains from patients with familial and non-familial Alzheimer''s disease (AD). We studied the density of NFT-free neurons, intracellular NFT (I-NFT), extracellular NFT (E-NFT) and total NFT (I-NFT plus E-NFT) in the six hippocampal subdivisions: cornu ammonis (CA) 1–CA4, subiculum and entorhinal cortex. The APP mutation cases showed significantly higher total NFT density in the CA1–CA2 region, and the PS-1 mutation cases also showed higher density of total NFT in the CA1–CA3 than non-familial cases. Moreover, high densities of the E-NFT contributed to these high total NFT densities. Non-familial AD cases showed a stereotypical NFT distribution with entorhinal accentuation in the hippocampus irrespective of E4 frequency. Thus, APP and PS-1 mutations predominantly affect the CA regions with profound neurodegeneration, which contributes early and severe clinical features of familial AD. [Copyright &y& Elsevier]

Abstract To explore more fully the relationship between neuronal death and neurofibrillary degeneration, unaffected neurons, intracellular neurofibrillary tangles (i-NFT) and extracellular NFT (e-NFT) in 22 patients with late-onset sporadic Alzheimer's disease (AD) were morphometrically evaluated in eight subdivisions of the hippocampal cortex, using the Gallyas hematoxylin-eosin stain. The subdivisions examined included CA4, CA3, CA2, CA1 (CA: cornu ammonis), prosubiculum (PRO), subiculum and presubiculum (PRE), parasubiculum (PARA) and the entorhinal cortex (ENT). The unaffected neuron density was significantly lower and both i-NFT and e-NFT densities were significantly higher in subdivisions other than CA4 and CA3 in AD patients compared with those in the aged controls. Unaffected neuron density was significantly, inversely correlated with e-NFT density and with total NFT density in all subdivisions except for PRE in AD patients. Especially in CA2, CA1, PRO and ENT, there were strong correlations between the neuron density and these NFT densities. Both unaffected neuron and e-NFT densities in CA1 and ENT were significantly correlated with the disease duration. The i/e-NFT ratio, an index of the degree and/or rate of progress of neuronal death via neurofibrillary degeneration, showed the lowest value in ENT in AD patients. The findings suggest that neuronal death via neurofibrillary degeneration starts earliest and/or most rapidly progresses in ENT. Furthermore, the i/e-NFT ratios in both ENT and CA1 were significantly correlated with the disease duration, suggesting that the neuronal death pattern in the two subdivisions parallels disease progression. [ABSTRACT FROM AUTHOR]