title: Caspase-6 activity in the CA1 region of the hippocampus induces age-dependent memory impairment.
abstract: Active Caspase-6 is abundant in the neuropil threads, neuritic plaques and neurofibrillary tangles of Alzheimer disease brains. However, its contribution to the pathophysiology of Alzheimer disease is unclear. Here, we show that higher levels of Caspase-6 activity in the CA1 region of aged human hippocampi correlate with lower cognitive performance. To determine whether Caspase-6 activity, in the absence of plaques and tangles, is sufficient to cause memory deficits, we generated a transgenic knock-in mouse that expresses a self-activated form of human Caspase-6 in the CA1. This Caspase-6 mouse develops age-dependent spatial and episodic memory impairment. Caspase-6 induces neuronal degeneration and inflammation. We conclude that Caspase-6 activation in mouse CA1 neurons is sufficient to induce neuronal degeneration and age-dependent memory impairment. These results indicate that Caspase-6 activity in CA1 could be responsible for the lower cognitive performance of aged humans. Consequently, preventing or inhibiting Caspase-6 activity in the aged may provide an efficient novel therapeutic approach against Alzheimer disease.
authors.affiliation: 1] Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Ch. Cote Ste-Catherine, Montreal, QC H3T 1E2, Canada [2] Department of Neurology and Neurosurgery, McGill University, 3775 University St., Montreal, QC H3A 2B4, Canada.
authors.forename: A C
authors.initials: AC
authors.lastname: LeBlanc
authors.affiliation: 1] Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Ch. Cote Ste-Catherine, Montreal, QC H3T 1E2, Canada [2] Department of Neurology and Neurosurgery, McGill University, 3775 University St., Montreal, QC H3A 2B4, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Ramcharitar
authors.affiliation: 1] Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Ch. Cote Ste-Catherine, Montreal, QC H3T 1E2, Canada [2] Department of Neurology and Neurosurgery, McGill University, 3775 University St., Montreal, QC H3A 2B4, Canada.
authors.forename: V
authors.initials: V
authors.lastname: Afonso
authors.affiliation: 1] Department of Neurology and Neurosurgery, McGill University, 3775 University St., Montreal, QC H3A 2B4, Canada [2] Montreal Neurological Institute, 3801 rue University, Montreal, QC H3A 2T5, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Hamel
authors.affiliation: 1] Rush Alzheimer's Disease Center, Rush University Medical Center, 600S. Paulina, Suite 1028, Chicago, IL, USA [2] Department of Neurological Sciences, Rush University Medical Center, 1725 West Harrison, Chicago, IL, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Bennett
authors.affiliation: 1] Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Ch. Cote Ste-Catherine, Montreal, QC H3T 1E2, Canada [2] Department of Neurology and Neurosurgery, McGill University, 3775 University St., Montreal, QC H3A 2B4, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Pakavathkumar
authors.affiliation: Department of Pathology, McGill University, and Montreal Children's Hospital, Montreal, QC H3A 2B4, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Albrecht
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000201:enzymology; D000818:Animals; D053178:Caspase 6 / Q000096:biosynthesis / Q000378:metabolism*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000201:enzymology*; D006801:Humans; D008297:Male; D008568:Memory / Q000502:physiology; D008569:Memory Disorders / Q000201:enzymology*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000201:enzymology*; D015398:Signal Transduction
chemical_list: D053178:Caspase 6