© J. Poirier 2022
Le noyeau de l’équipe et les publications récentes
Brain   Reinnervation   and   Apolipoprotein   E   Neurobiology:   The   initial   phase   of   our   research   program   has   been   to   identify   key mRNAs   involved   in   synaptic   remodelling   in   the   injured   adult   rodent   brain.   In   an   article   published   in   Proc.   Natl. Acad.   Sci.   87:303 ,   we documented   the   fact   that   a   limited   numbers   of   mRNAs   of   moderate   prevalence   exhibit   significant   induction   during   the   active   phase   of reinnervation    in    the    experimentally    deafferented    rat    hippocampus    (a    partial    model    of   Alzheimer's    disease    pathology).   The    most important   transcript   identified   during   follow-up   cDNA   screenings   turned   out   to   be   a   protein   known   as   apolipoprotein   E   (apoE),   a   well- characterized cholesterol transporter produced locally in the brain. Apolipoprotein   E4   and   the   Pathophysiology   of   Alzheimer’s   disease :   In   a   follow-up   series   of   studies   in   neurodegenerative   diseases, we   published   a   breakthrough   report   in   the   Lancet   342:   697    where   we   reported   that   sporadic   cases   with   Alzheimer's   disease   (AD) exhibit   an   abnormally   high   incidence   of   a   normally   rare   apoE   allele   referred   to   as   the   apoE4.   Follow-up   publications   by   our   team demonstrated   a   potent   apoE4-gene   dose   effect   on   :   a)   age   of   onset,   b)   rate   of   progression,   c)   risk   of   developing   the   disease   and   more importantly, d) on the cholinergic status and integrity in the brain of sporadic Alzheimer’s disease subjects: Proc. Natl. Acad. Sci. 92 :  12260,  Lancet  347: 1091 J.A.M.A. 278: 1349 , Proc. Natl. Acad. Sci. 98: 10966 .   Apolipoprotein   E   influences   the   Beta-Amyloid   Neurotoxicity   and   Metabolism:   In   more   recent   years,   we   uncovered   the   biological connection   linking   the   so-called   beta   amyloid   cascade   hypothesis   of   AD   and   apolipoprotein   E   metabolism   in   the   pathophysiology   of Alzheimer’s   disease.   Using   various   techniques,   models   and   approaches,   we   documented   the   apoE/beta   amyloid   relationship   in   vitro   and in   vivo .   The   studies   were   published   in   Nature      387:   500 ,      J.   Neurochem.      66:2410 ,   J.   Neurochem.      70:1466 ,   Brain   Research   Reviews 27: 199 Apolipoprotein   E4: A   Pharmacogenomic   Marker   of   Drug   Efficacy   in Alzheimer’s   disease:   Our   modest   but   significant   contribution to   the   emerging   field   of   the   pharmacogenomics   prompted   several   pharmaceutical   corporations   (Eli   Lilly,   Bayer,   Parke   Davis,   Novartis and   Smith   Kline   Beecham)   to   re-evaluate   their   clinical   drug   trial   designs   to   include   an   apoE   genotype   arm.   We   and   others   have documented   on   multiple   occasions   the   fact   that   the   efficacy   of   several   memory   enhancers   (especially   cholinomimetics)   are   highly dependent    upon    the    individual’s    apoE    or    BuChE    K    genotypes    Proc.    Natl.   Acad.    Sci.        92:    12260 ,    Neurology    50:    669,     Curr. Pharmacogen.   8:   63    this   key   contribution   to   canadian   translation   research   effort   was   recognized   by   the   Galien   1996   Prize   and   Genesis Awards 2010 Cholesterol   Metabolism   as   Therapeutic   Target   for   the   Treatment   of   Alzheimer’s   Disease:   As   early   as   1993,   we   proposed   that   the reduction   in   apoE   concentrations   reported   in   the   blood   and   brain   of   apoE4   allele   carriers   could   be   alleviated   by   drugs   that   specifically promote   apoE   synthesis   and   secretion   in   the   CNS.   Building   on   the   approach,   we   identified   three   different   agents   (out   of   several hundreds) with strong apoE inducing capacity: estrogen, indomethacin and probucol ( Eur. J. Neurosci. 18: 1 , Neuroscience 121: 99 ,   Alz.   Dem.      4:   591 ,   Curr   Alz   Res   5:33 )   .   Independently   of   this   work,   these   three   compounds   had   been   shown   to   reduce   the   risk   of developing   AD   in   several   epidemiological   studies   ran   in   the   US,   Europe   and   Asia.   As   a   consequence,   we   choose   to   focus   on   the   drug Probucol,   a   potent   cholesterol-lowering   agent   for   efficacy   and   safety   reasons.   In   a   small   proof-of-principal   study   performed   in   Montreal ( Adv.   Behav.   Biol.   51:   39 ,      Trends   Mol.   Medicine   9:94 ,   Neurobiol.   Aging   2014 ),   we   discovered   that   a   6-month   treatment   with Probucol   in   mild-tomoderate AD   stopped   disease   progression   in   the   majority   of   the   12   patients   enrolled   in   the   study   and   “improved”   the activities of daily living for the entire group. CSF   Biomarkers   of   AD   Progression   in   “at   risk”   Asymptomatic   Subjects :   Combining   genomic   information   (GWAS,   eQTL), multiple   cohort   analyses   and   new   sensitive   bioassays   (OLINK,   LC/MS   /MS,   SimoA   and   Luminex),   we   successfully   documented   a series   of   novel   CNS   biomarkers   and   genetic   risk   factors   that   modulate   AD   pathology   in   the   pre-symptomatic   phase   of   AD   ( JAMA Neurol. 75:5:608-619, Alzheimer & Dementia 14:787-796, Nature Comm.10:2240-2255, Alzheimer and Dementia 15: 742-753 )
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