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

Accumulation of amyloid-beta (A beta) peptide is believed to play a central role in the pathogenesis of Alzheimer's disease (AD). Lowering A beta levels in the brain may thus improve synaptic and cognitive deficits observed in AD patients. In the non-amyloidogenic pathway, the amyloid-beta precursor protein (APP) is cleaved within the A beta peptide sequence by alpha-secretases, giving rise to the potent neurotrophic N-terminal fragment sAPP alpha. We have previously reported that gelatinase B/matrix metalloproteinase 9 (MMP-9), a matrix metalloproteinase critically involved in neuronal plasticity, acts as alpha-secretase both in vitro and in vivo and reduces A beta 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 sAPP alpha levels and decreased A beta 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. (C) 2014 Elsevier Inc. All rights reserved.