Research Article: Reducing Amyloid Plaque Burden via Ex Vivo Gene Delivery of an Aβ-Degrading Protease: A Novel Therapeutic Approach to Alzheimer Disease

Date Published: August 28, 2007

Publisher: Public Library of Science

Author(s): Matthew L Hemming, Michaela Patterson, Casper Reske-Nielsen, Ling Lin, Ole Isacson, Dennis J Selkoe, Sam Gandy

Abstract: BackgroundUnderstanding the mechanisms of amyloid-β protein (Aβ) production and clearance in the brain has been essential to elucidating the etiology of Alzheimer disease (AD). Chronically decreasing brain Aβ levels is an emerging therapeutic approach for AD, but no such disease-modifying agents have achieved clinical validation. Certain proteases are responsible for the catabolism of brain Aβ in vivo, and some experimental evidence suggests they could be used as therapeutic tools to reduce Aβ levels in AD. The objective of this study was to determine if enhancing the clearance of Aβ in the brain by ex vivo gene delivery of an Aβ-degrading protease can reduce amyloid plaque burden.Methods and FindingsWe generated a secreted form of the Aβ-degrading protease neprilysin, which significantly lowers the levels of naturally secreted Aβ in cell culture. We then used an ex vivo gene delivery approach utilizing primary fibroblasts to introduce this soluble protease into the brains of β-amyloid precursor protein (APP) transgenic mice with advanced plaque deposition. Brain examination after cell implantation revealed robust clearance of plaques at the site of engraftment (72% reduction, p = 0.0269), as well as significant reductions in plaque burden in both the medial and lateral hippocampus distal to the implantation site (34% reduction, p = 0.0020; and 55% reduction, p = 0.0081, respectively).ConclusionsEx vivo gene delivery of an Aβ-degrading protease reduces amyloid plaque burden in transgenic mice expressing human APP. These results support the use of Aβ-degrading proteases as a means to therapeutically lower Aβ levels and encourage further exploration of ex vivo gene delivery for the treatment of Alzheimer disease.

Partial Text: The pathologic hallmarks of Alzheimer disease (AD) are extracellular plaques of amyloid-β protein (Aβ) and intraneuronal neurofibrillary tangles of tau protein, both of which accumulate in brain regions mediating memory and cognition [1]. All known early-onset, inherited forms of AD arise from mutations in the β-amyloid precursor protein (APP), from which the Aβ peptide is generated, or the presenilins, which are the proteases that effect the cleavage of APP, which liberates Aβ. Both amyloid plaques and soluble Aβ oligomers are believed to have neurotoxic effects [2,3], and evidence suggests that Aβ neurotoxicity can promote neurofibrillary tangle formation [4,5]. Though approved treatments for AD ameliorate only the symptoms, potentially disease-modifying interventions under development focus on therapeutically lowering Aβ production [6] or enhancing Aβ clearance [7,8].

Various approaches to lowering Aβ levels within the brain have come to represent the central focus in AD therapeutic development. In this study, we describe the use of ex vivo gene therapy as a viable approach to reducing Aβ levels utilizing a modified Aβ-degrading protease. Replacing the transmembrane domain of the normally membrane-anchored NEP with a signal peptide resulted in the robust secretion of an enzymatically active protease. When syngenic fibroblasts modified to produce sNEP were engrafted into aged APP transgenic mice, the majority of the plaque burden surrounding the graft site was proteolytically cleared. Distal to the graft, in both the medial and lateral hippocampus, significant reductions in plaque burden were also observed as a result of sNEP gene delivery. These results demonstrate the utility of locally elevating the expression of a secreted Aβ-degrading protease as a potential therapeutic approach for AD.

Source:

http://doi.org/10.1371/journal.pmed.0040262

 

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