Autor(es):
Barros-Viegas, Ana Teresa ; Carmona, Vitor ; Ferreiro, Elisabete ; Guedes, Joana ; Cardoso, Ana Maria S. ; Cunha, Pedro ; Almeida, Luís Pereira de ; Oliveira, Catarina Resende de ; Magalhães, João Pedro de ; Peça, João ; Cardoso, Ana Luísa
Data: 2020
Identificador Persistente: https://hdl.handle.net/10316/106459
Origem: Estudo Geral - Universidade de Coimbra
Assunto(s): Alzheimer’s disease; miR-31; gene therapy; lentiviral vector; APP; BACE1; amyloid-β peptide; cognitive function; memory
Descrição
Alzheimer's disease (AD) is the most common form of dementia worldwide, characterized by progressive memory impairment, behavioral changes, and, ultimately, loss of consciousness and death. Recently, microRNA (miRNA) dysfunction has been associated with increased production and impaired clearance of amyloid-β (Aβ) peptides, whose accumulation is one of the most well-known pathophysiological markers of this disease. In this study, we identified several miRNAs capable of targeting key proteins of the amyloidogenic pathway. The expression of one of these miRNAs, miR-31, previously found to be decreased in AD patients, was able to simultaneously reduce the levels of APP and Bace1 mRNA in the hippocampus of 17-month-old AD triple-transgenic (3xTg-AD) female mice, leading to a significant improvement of memory deficits and a reduction in anxiety and cognitive inflexibility. In addition, lentiviral-mediated miR-31 expression significantly ameliorated AD neuropathology in this model, drastically reducing Aβ deposition in both the hippocampus and subiculum. Furthermore, the increase of miR-31 levels was enough to reduce the accumulation of glutamate vesicles in the hippocampus to levels found in non-transgenic age-matched animals. Overall, our results suggest that miR-31-mediated modulation of APP and BACE1 can become a therapeutic option in the treatment of AD.
This work was financed by the European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Programme under the project CENTRO-01-0145-FEDER-000008: BrainHealth 2020 and through the COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation and Portuguese national funds via FCT - Fundação para a Ciência e a Tecnologia, under the project POCI- 01-0145-FEDER-007440 (reference UID/NEU/04539/2013). This work was also supported by the FCT Investigator Programme (IF/ 00694/2013 to J.P.), the Marie Curie Carrier Integration Grant (PCIG13-GA-2013-618525 to J.P.), HEALTHYAGING 2020 (CENTRO-01-0145-FEDER-000012 to A.T.B.-V.), and Bial Foundation Grant 264/16. A.T.B.-V., J.G., and A.L.C. are recipients of fellowships from the FCT (Grants PTDC/BIM-MEC/0651/2012, SFRH/ BPD/120611/2016, and SFRH/BPD/108312/2015).
