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Characterization of TDP-43 changes during normal aging: a postmortem study

Grant number: 11/19833-7
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): August 01, 2012
Effective date (End): April 30, 2015
Field of knowledge:Biological Sciences - Morphology - Histology
Principal Investigator:Lea Tenenholz Grinberg
Grantee:Camila Nascimento Mantelli
Home Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The elderly population is growing worldwide, especially in developing countries. It is happening due to the progressive decline of fertility and mortality and the improvement in quality of life of these populations. Among the aging related diseases, neurodegenerative diseases are one of the most prevalent and disabling. Neurodegenerative diseases have several common features, including the accumulation of abnormal specific proteins in the brain. In 2006, a DNA-binding protein that has 43-kDa (TDP-43) was identified as the major abnormal protein in cases of Frontotemporal Lobar Degeneration (FTLD). Association of TDP-43 with FTLDs was a surprising finding and little was known about its action mechanism, function or behavior in normal aging. Despite the advances in TDP-43 studies, normative basis are still lacking. The threshold between its physiological and pathological role is still unknown. Normative controls although necessary are difficult to produce due to the increasing drop of autopsy rates worldwide. For this reason, the collection of the Brain Bank of the Brazilian Aging Brain Study Group (BBBABSG) on University of Sao Paulo Medical School (MSUSP) is a window of opportunity for generating such important basis. The BBBABSG comprise a large number of well-characterized brains of elderly non-demented subjects, which enables us to further study the non-pathological aging human brain. We propose to analyze systematically the distribution of phosphorylated (abnormal) TDP-43 protein in normal human aging in a large archived sample of 400 subjects. Subjects were previously classified clinically and anatopatologically as normal controls and subjected to the exact same protocol. Selected areas will be immunostained against phosphorylated TDP-43 protein. We will analyze frequently vulnerable areas to FTLD-TDP-43. TDP-43 inclusions will be evaluated by semi-quantitative methods, per area. These analyzes will be conducted according to stereological principles with the use of Image J software. Areas of interest will be compared using linear statistics models. Our proposal is to reveal whether the TDP-43 modifications are necessarily synonymous of disease and whether there are preferred vulnerability areas to initial developmental of disease, or not. Although apparently this study is essentially descriptive, similar approaches resulted in understanding of early stages of neurodegenerative diseases, such as Alzheimer's disease. We will also characterize TDP-43 inclusions by biochemical essays. In these experiments we will verify whether TDP-43 modifications have a similar biochemical pattern that has been seen in cases of FTLD-TDP. For this study we will carry out immunoblotting. We will use FTLD cases (n=10) in both experiments. We believe that this study can accelerate our understanding of TDP-43 changes during ages and assist us in determining targets for early stage interventions. (AU)

Articles published in other media outlets (7 total):
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Awesome Investors: Alzheimer’s disease destroys neurons that keep us awake (12/Aug/2019)
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Neuroscience News (EUA): Alzheimer’s disease destroys neurons that keep us awake (12/Aug/2019)
Awesome Capital: Alzheimer’s disease destroys neurons that keep us awake (12/Aug/2019)
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UCSF - University of California San Francisco (EUA): Alzheimer’s disease destroys neurons that keep us awake (12/Aug/2019)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
NASCIMENTO, C.; DI LORENZO ALHO, A. T.; BAZAN CONCEICAO AMARAL, C.; LEITE, R. E. P.; NITRINI, R.; JACOB-FILHO, W.; PASQUALUCCI, C. A.; HOKKANEN, S. R. K.; HUNTER, S.; KEAGE, H.; KOVACS, G. G.; GRINBERG, L. T.; SUEMOTO, C. K. Prevalence of transactive response DNA-binding protein 43 (TDP-43) proteinopathy in cognitively normal older adults: systematic review and meta-analysis. NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, v. 44, n. 3, p. 286-297, APR 2018. Web of Science Citations: 10.
RODRIGUEZ, ROBERTA DIEHL; SUEMOTO, CLAUDIA KIMIE; MOLINA, MARIANA; NASCIMENTO, CAMILA FERNANDES; LEITE, RENATA ELAINE PARAIZO; DE LUCENA FERRETTI-REBUSTINI, RENATA ELOAH; FARFEL, JOSE MARCELO; HEINSEN, HELMUT; NITRINI, RICARDO; UEDA, KENJI; PASQUALUCCI, CARLOS AUGUSTO; JACOB-FILHO, WILSON; YAFFE, KRISTINE; GRINBERG, LEA TENENHOLZ. d Argyrophilic Grain Disease: Demographics, Clinical, and Neuropathological Features From a Large Autopsy Study. JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY, v. 75, n. 7, p. 628-635, JUL 2016. Web of Science Citations: 13.
NASCIMENTO, CAMILA; SUEMOTO, CLAUDIA K.; RODRIGUEZ, ROBERTA D.; DI LORENZO ALHO, ANA TEREZA; LEITE, RENATA P.; FARFEL, JOSE MARCELO; GONCALVES PASQUALUCCI, CARLOS AUGUSTO; JACOB-FILHO, WILSON; GRINBERG, LEA T. Higher Prevalence of TDP-43 Proteinopathy in Cognitively Normal Asians: A Clinicopathological Study on a Multiethnic Sample. Brain Pathology, v. 26, n. 2, p. 177-185, MAR 2016. Web of Science Citations: 13.
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
MANTELLI, Camila Nascimento. Characterization of TDP-43 changes during normal aging: a human brain post-mortem study. 2015. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina São Paulo.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.