The MPTP neurotoxic lesion model of Parkinson's disease activates the apolipoprotein E cascade in the mouse brain

Abstract

Apolipoprotein E (apoE) is recognized as a key actor in brain remodeling. It has been shown to increase after peripheral and central injury, to modulate reparative capacity in neurodegenerative conditions like Alzheimer's disease (AD) and to be associated with a number of other neurodegenerative diseases. This particular function of apoE has been postulated to underlie the robust association with risk and age at onset of AD. ApoE associations studies with Parkinson's disease (PD), the second most prevalent neurodegenerative disease, have generated contradictory results but associations with age at onset and dementia in PD stand out. We investigate here whether apoE is involved in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced degeneration that models PD-like deafferentation of the striatum in the mouse and participates in compensatory reinnervation mechanisms. We examined the modifications in gene expression and protein levels of apoE and its key receptors, the low density lipoprotein receptor (LDLR) and the LDLR-related protein (LRP), as well as the reactive astrocyte marker glial fibrillary acidic protein (GFAP) in different brain structures throughout the degenerative and reactive regenerative period. In the striatum, upregulations of GFAP, apoE and LRP mRNAs at 1 day post-treatment were associated with marked decreases in dopamine (DA) levels, loss in tyrosine hydroxylase protein content, as well as to a compensatory increase in dopaminergic metabolism. Subsequent return to near control levels coincided with indications of reinnervation in the striatum: all consistent with a role of apoE during the degenerative process and regenerative period. We also found that this cascade was activated in the hippocampus and more so than in the striatum, with a particular contribution of LDLR expression. The hippocampal activation did not correlate with substantial neurochemical reductions but appears to reflect local subtle alteration of DA metabolism and the regulation of plasticity-related event in this structure. This study provides first evidence of an activation of the apoE/apoE receptors cascade in a mouse model of PD, specifically in the MPTP-induced deafferentation of the striatum. Results are also quite consistent with the postulated role of apoE in brain repair but, raise the issue of possible lesion- and region-specific alterations in gene expression.