Abstract
Transplantation of neural stems cells (NSCs) could be a useful means to deliver biologic therapeutics for late-stage Alzheimer's disease (AD). In this study, we conducted a small preclinical investigation of whether NSCs could be modified to express metalloproteinase 9 (MMP9), a secreted protease reported to degrade aggregated Aβ peptides that are the major constituents of the senile plaques. Our findings illuminated three issues with using NSCs as delivery vehicles for this particular application. First, transplanted NSCs generally failed to migrate to amyloid plaques, instead tending to colonize white matter tracts. Second, the final destination of these cells was highly influenced by how they were delivered. We found that our injection methods led to cells largely distributing to white matter tracts, which are anisotropic conduits for fluids that facilitate rapid distribution within the CNS. Third, with regard to MMP9 as a therapeutic to remove senile plaques, we observed high concentrations of endogenous metalloproteinases around amyloid plaques in the mouse models used for these preclinical tests with no evidence that the NSC-delivered enzymes elevated these activities or had any impact. Interestingly, MMP9-expressing NSCs formed substantially larger grafts. Overall, we observed long-term survival of NSCs in the brains of mice with high amyloid burden. Therefore, we conclude that such cells may have potential in therapeutic applications in AD but improved targeting of these cells to disease-specific lesions may be required to enhance efficacy.
Highlights
The extracellular deposition of the amyloid beta peptide (Ab) is a requisite pathology for diagnosis of Alzheimer’s disease (AD) [1,2]
In summary, we have performed a preclinical assessment of the ease with which neural stems cells (NSCs) can be manipulated to express biologic therapeutics, and whether such cells can form significant engraftments in the brains of mice that exhibit Alzheimer-type amyloid pathology
We demonstrate that NSCs can be modified to express modified to express metalloproteinase 9 (MMP9) and that NSCs can form significant grafts that survive for long periods, we observed no indication that the cells delivered a sufficient quantity of enzyme to be efficacious
Summary
The extracellular deposition of the amyloid beta peptide (Ab) is a requisite pathology for diagnosis of Alzheimer’s disease (AD) [1,2]. Wang et al demonstrated that amyloid plaque burden in this model can be partially ameliorated by passive transfer of antibody to Ab peptide [7] suggesting that additional interventions may promote clearance of amyloid pathology. Current opinions on treatment of AD lean toward early therapeutic interventions, including delivery of inhibitors of c- and, or, b-secretase [4]. While these approaches hold promise if issues of toxicity can be overcome, they offer little hope for patients with fulminant, late-stage disease
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