title: Age-dependent, non-cell-autonomous deposition of amyloid from synthesis of β-amyloid by cells other than excitatory neurons.
abstract: Rare, familial, early-onset autosomal dominant forms of familial Alzheimer's disease (FAD) are caused by mutations in genes encoding β-amyloid (Aβ) precursor protein (APP), presenilin-1 (PS1), and presenilin-2. Each of these genes is expressed ubiquitously throughout the CNS, but a widely held view is that excitatory neurons are the primary (or sole) source of the Aβ peptides that promote synaptic dysfunction and neurodegeneration. These efforts notwithstanding, APP and the enzymes required for Aβ production are synthesized by many additional cell types, and the degree to which those cells contribute to the production of Aβ that drives deposition in the CNS has not been tested. We generated transgenic mice in which expression of an ubiquitously expressed, FAD-linked mutant PSEN1 gene was selectively inactivated within postnatal forebrain excitatory neurons, with continued synthesis in all other cells in the CNS. When combined with an additional transgene encoding an FAD-linked APP "Swedish" variant that is synthesized broadly within the CNS, cerebral Aβ deposition during aging was found to be unaffected relative to mice with continued mutant PS1 synthesis in excitatory neurons. Thus, Aβ accumulation is non-cell autonomous, with the primary age-dependent contribution to cerebral Aβ deposition arising from mutant PS1-dependent cleavage of APP within cells other than excitatory neurons.
authors.affiliation: Department of Neurobiology, University of Chicago, Chicago, Illinois 60637, and Department of Neurology, Genetics and Aging Research Unit, Massachusetts General Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129-2060.
authors.forename: Karthikeyan
authors.initials: K
authors.lastname: Veeraraghavalu
authors.forename: Can
authors.initials: C
authors.lastname: Zhang
authors.forename: Xiaoqiong
authors.initials: X
authors.lastname: Zhang
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
authors.forename: Sangram S
authors.initials: SS
authors.lastname: Sisodia
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis*; D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000145:classification / Q000378:metabolism / Q000473:pathology*; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology*
chemical_list: D016564:Amyloid beta-Protein Precursor
keywords: APP; amyloid deposition; dementia; mouse model; neurodegeneration; presenilin