title: Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice.
abstract: Progressive memory loss and cognitive dysfunction are the hallmark clinical features of Alzheimer's disease (AD). Identifying the molecular triggers for the onset of AD-related cognitive decline presently requires the use of suitable animal models, such as the 3xTg-AD mice, which develop both amyloid and tangle pathology. Here, we characterize the onset of learning and memory deficits in this model. We report that 2-month-old, prepathologic mice are cognitively unimpaired. The earliest cognitive impairment manifests at 4 months as a deficit in long-term retention and correlates with the accumulation of intraneuronal Abeta in the hippocampus and amygdala. Plaque or tangle pathology is not apparent at this age, suggesting that they contribute to cognitive dysfunction at later time points. Clearance of the intraneuronal Abeta pathology by immunotherapy rescues the early cognitive deficits on a hippocampal-dependent task. Reemergence of the Abeta pathology again leads to cognitive deficits. This study strongly implicates intraneuronal Abeta in the onset of cognitive dysfunction.
authors.affiliation: Department of Neurobiology and Behavior and Center for the Neurobiology of Learning and Memory, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Billings
authors.forename: Salvatore
authors.initials: S
authors.lastname: Oddo
authors.forename: Kim N
authors.initials: KN
authors.lastname: Green
authors.forename: James L
authors.initials: JL
authors.lastname: McGaugh
authors.forename: Frank M
authors.initials: FM
authors.lastname: LaFerla
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000378:metabolism*; D000818:Animals; D003072:Cognition Disorders / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D005260:Female; D006624:Hippocampus / Q000737:chemistry / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000737:chemistry / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides