Neuroprotective role of MMP-9 overexpression in the brain of Alzheimer's 5xFAD mice

Apostolia Fragkouli, Effie C. Tsilibary, Athina K. Tzinia

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Accumulation of amyloid-β (Αβ) peptide is believed to play a central role in the pathogenesis of Alzheimer's disease (AD). Lowering Aβ levels in the brain may thus improve synaptic and cognitive deficits observed in AD patients. In the non-amyloidogenic pathway, the amyloid-β precursor protein (APP) is cleaved within the Aβ peptide sequence by α-secretases, giving rise to the potent neurotrophic N-terminal fragment sΑPPα. We have previously reported that gelatinase B/matrix metalloproteinase 9 (MMP-9), a matrix metalloproteinase critically involved in neuronal plasticity, acts as α-secretase both in vitro and in vivo and reduces Aβ levels in vitro. In the present study, we demonstrate that neuronal overexpression of MMP-9 in a transgenic AD mouse model harboring five familial AD-related mutations (5xFAD) resulted in increased sAPPα levels and decreased Aβ oligomers without affecting amyloid plaque load in the brain. Functionally, overexpression of MMP-9 prevented the cognitive deficits displayed by 5xFAD mice, an improvement that was accompanied by increased levels of the pre-synaptic protein synaptophysin and mature brain-derived neurotrophic factor (BDNF) in the brain. These results suggest that in vivo activation of endogenous MMP-9 could be a promising target for interference with development and/or progression of AD.

Original languageEnglish (US)
Pages (from-to)179-189
Number of pages11
JournalNeurobiology of Disease
Volume70
DOIs
StatePublished - Oct 2014

Bibliographical note

Funding Information:
The work has been supported in part by NCRS Demokritos and COST BM1001 (ECM Net).

Keywords

  • 5xFAD mouse model
  • Alzheimer's disease
  • Amyloid beta
  • MMP-9
  • α-Secretase

Fingerprint Dive into the research topics of 'Neuroprotective role of MMP-9 overexpression in the brain of Alzheimer's 5xFAD mice'. Together they form a unique fingerprint.

Cite this