Sérgio U. Dani

Progressive formation of neuritic plaques and neurofibrillary tangles is exponentially related to age and neuronal size. A morphometric study of three geographically distinct series of aging people

Neuronal size and the incidence of neuritic plaques (NPs) and neurofibrillary tangles (NFTs) were morphometrically and quantitatively studied in the entorhinal cortex of 300 autopsied individuals without dementia in three geographically distinct series (Brazil, Germany and Japan), and an additional series including 30 clinically diagnosed Alzheimers disease patients. The mean ages at onset of NPs and NFTs were similar between the three normal series, and the incidence of NPs and NFTs increased exponentially with age, but at different rates. A correlation was found between larger neuronal size and higher incidence of NPs and NFTs. Neuronal size distribution largely seemed to account for the differences between the series. While the onset of neurodegeneration may be tightly programmed, i.e., in a species-specific manner, our data support the idea that the incidence of NPs and NFTs and the progression from NPs to NFTs may vary remarkably, depending on neuronal size.

Somatic Mutation Analysis of the APP and Presenilin 1 and 2 Genes in Alzheimer's Disease Brains

The molecular basis for sporadic Alzheimer disease (AD) remains largely unknown. We hypothesized that in some cases of sporadic AD, a somatic mutation in an embryonic cell committed to neuronal development within the amyloid precursor protein (APP), the presenilin 1 (PS-1) or the presenilin 2 (PS-2) genes (genes known to be involved in familial AD) may result in AD phenotype. Using PCR, denaturing gradient gel electrophoresis (DGGE), restriction enzyme digest and direct DNA sequencing, we analyzed these genes in 99 brain tissues from patients with histopathologically proven AD. One brain sample showed a mutation within the PS-1 gene, His163 Arg, later shown to be a germline mutation. No other migration abnormalities were demonstrated in any sample in exon 16 or 17 of the APP gene or the coding exons of the PS-1 gene. Restriction digest pattern was normal with regard to the predominant PS-2 gene mutation (N141I). A known mutation in the APP gene, as well as novel mutations within the PS-1 gene were easily detected by DGGE (Reznick Wolf et al. manuscript submitted). We conclude that the genes that are involved in familial AD do not display somatic mutations in the brains of sporadic AD patients, and that other molecular mechanisms are probably involved in the pathogenesis of sporadic AD.

Different Rates of Neuronal Degeneration: An Exquisite Variation of the 'Cascade' Hypothesis

This morphometric, quantitative and correlative multivariate study of the hippocampal formation in human brains from two distinct normal aging populations provides an additional support to the notion that neuritic plaques (NP) are an earlier stage of the pathological process underlying neurofibrillary tangle (NFT) formation. It is shown that the rate of transformation of NP-affected neurons into NFT-bearing neurons may vary remarkably between distinct populations. In addition, it is put forward that different rates of neuronal degeneration may be one of the explanations for the existence of conflicting hypotheses regarding pathogenesis of NP and NFT and the relationships of these important histological markers to psychical deterioration.

Pairomics, the omics way to mate choice.

The core aspects of the biology and evolution of sexual reproduction are reviewed with a focus on the diploid, sexually reproducing, outbreeding, polymorphic, unspecialized, altricial and cultural human species. Human mate choice and pair bonding are viewed as central to individuals’ lives and to the evolution of the species, and genetic assistance in reproduction is viewed as a universal human right. Pairomics is defined as an emerging branch of the omics science devoted to the study of mate choice at the genomic level and its consequences for present and future generations. In pairomics, comprehensive genetic information of individual genomes is stored in a database. Computational tools are employed to analyze the mating schemes and rules that govern mating among the members of the database. Mating models and algorithms simulate the outcomes of mating any given genome with each of a number of genomes represented in the database. The analyses and simulations may help to understand mating schemes and their outcomes, and also contribute a new cue to the multicued schemes of mate choice. The scientific, medical, evolutionary, ethical, legal and social implications of pairomics are far reaching. The use of genetic information as a search tool in mate choice may influence our health, lifestyle, behavior and culture. As knowledge on genomics, population genetics and gene–environment interactions, as well as the size of genomic databases expand, so does the ability of pairomics to investigate and predict the consequences of mate choice for the present and future generations.

A Multivariate Approach to the Relationship between Aging, RNA Depletion and the Incidence of Plaques and Tangles

In order to study the relationship between changes in total cytoplasmic RNA and the incidence of neuritic plaques (NP) and neurofibrillary tangles (NFT) in the aging human brain, a series of parahippocampal gyri (PHG) was obtained, post mortem, from 50 aging, mostly non‐Alzheimer disease human brains, grouped in five decades of life. Absolute and relative NP and NFT counts in silver stained preparations were performed with the aid of a semi‐automated image analysis system, and total cytoplasmic RNA was estimated in azure b (ab) preparations. Progressive ab‐RNA depletion corresponded to the decades of life in which the incidences of NP and NFT increased significantly. Multivariate analysis of variance (MANOVA) indicated not only isolated effects of increasing age and decreasing mean ab‐RNA, upon the incidence of NP, but also interactive effects of the two former parameters. In addition, highly significant isolated and interactive effects of age and mean ab‐RNA decrease were also observed upon the incidence of NFT. It is put forward that the rate at which total neuronal cytoplasmic RNA (mainly rRNA species) is reduced may play an important part in the pathophysiology of the neuronal degeneration as marked histologically by the onset of NP and NFT.