Regular Article The MPTP neurotoxic lesion model of Parkinson's disease activates the apolipoprotein E cascade in the mouse brain D. Domenger a , D. Dea a , L. Theroux a , L. Moquin a , A. Gratton a , J. Poirier a, b, ⁎ a Douglas Mental Health University Institute, 6875 Lasalle Blvd, Verdun, Quebec, Canada H4H 1R3 b McGill University Center for Studies in Aging, 6825 Lasalle Blvd, Verdun, Quebec, Canada H4H 1R3 abstract article info Article history: Received 25 August 2011 Revised 5 November 2011 Accepted 22 November 2011 Available online 3 December 2011 Keywords: Apolipoprotein E Parkinson's disease MPTP GFAP LDLR LRP Compensatory mechanisms Reinnervation Mouse model Dopamine 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 degen- eration that models PD-like deafferentation of the striatum in the mouse and participates in compensatory rein- nervation 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 deaf- ferentation 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. © 2011 Published by Elsevier Inc. Introduction Parkinson's disease (PD), the most prevalent neuromotor disease and second most prevalent age-related neurodegenerative disease after Alzheimer's disease (AD), is characterized by a progressive and irremediable loss of dopaminergic neurons in the substantia nigra (SN) (Ehringer and Hornykiewicz, 1960). One central projection of these neurons particularly affected in PD, targets precisely the cau- date and putamen nuclei of the basal ganglia, corresponding to the striatum in rodents, where it exerts an important modulation of motor behavior. PD is also characterized by a substantial decrease of dopamine (DA) in the striatum (St) and in fact, some evidence sug- gest that the loss of dopaminergic terminals and synapses in the stria- tum occurs prior to the death of the cell bodies in the SN in PD (Bernheimer et al., 1973) and in PD models in mice (Wu et al., 2003). The clinical symptoms of PD emerge when striatal DA levels are reduced by 70 to 80%, and roughly half of the nigral DA neurons have died (Bernheimer et al., 1973); consistent with the notion that compensato- ry mechanisms succeed at delaying the appearance of the well-known disabling motor symptoms for some time. Particularly relevant is the spontaneous reactive reinnervation following the loss of DAergic termi- nals in the striatum. Multiple demonstrations of regrowth of DAergic fi- bers and formation of new synapses have been reported in the nigrostriatal system in response to experimental degeneration in ani- mal models of parkinsonism (Bezard et al., 2000; Blanchard et al., Experimental Neurology 233 (2012) 513–522 Abbreviations: 5-HT, serotonin; A, adrenaline; AD, Alzheimer's disease; apoE, apolipo- proteine E; Cb, cerebellum; DA, dopamine; DHBA, 3,4-dihydroxybenzylamine; DOPAC, 3,4-dihydroxyphenylacetic acid; ECL, entorhinal cortex lesion; FCx, frontal cortex; GFAP, glial fibrillary acidic protein; HPC, hippocampus; LDLR, low density lipoprotein receptor; LRP, low density lipoprotein receptor -related protein; MPTP, 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine; n.s., non-significant; NA, noradrenaline; PD, Parkinson's dis- ease; pt, post-treatment; qRT-PCR, quantitative real time-polymerase chain reaction; SN, substantia nigra; St, striatum; TH, tyrosine hydroxylase. ⁎ Corresponding author at: Douglas Mental Health University Institute, 6875 Lasalle Blvd, Verdun, Quebec, Canada H4H 1R3. Fax: +1 514 888 4094. E-mail address: judes.poirier@mcgill.ca (J. Poirier). 0014-4886/$ – see front matter © 2011 Published by Elsevier Inc. doi:10.1016/j.expneurol.2011.11.031 Contents lists available at SciVerse ScienceDirect Experimental Neurology journal homepage: www.elsevier.com/locate/yexnr