title: Early hyperactivity in lateral entorhinal cortex is associated with elevated levels of AβPP metabolites in the Tg2576 mouse model of Alzheimer's disease.
abstract: Alzheimer's disease (AD) is a neurodegenerative disorder which is the most common cause of dementia in the elderly today. One of the earliest symptoms of AD is olfactory dysfunction. The present study investigated the effects of amyloid β precursor protein (AβPP) metabolites, including amyloid-β (Aβ) and AβPP C-terminal fragments (CTF), on olfactory processing in the lateral entorhinal cortex (LEC) using the Tg2576 mouse model of human AβPP over-expression. The entorhinal cortex is an early target of AD related neuropathology, and the LEC plays an important role in fine odor discrimination and memory. Cohorts of transgenic and age-matched wild-type (WT) mice at 3, 6, and 16months of age (MO) were anesthetized and acute, single-unit electrophysiology was performed in the LEC. Results showed that Tg2576 exhibited early LEC hyperactivity at 3 and 6MO compared to WT mice in both local field potential and single-unit spontaneous activity. However, LEC single-unit odor responses and odor receptive fields showed no detectable difference compared to WT at any age. Finally, the very early emergence of olfactory system hyper-excitability corresponded not to detectable Aβ deposition in the olfactory system, but rather to high levels of intracellular AβPP-CTF and soluble Aβ in the anterior piriform cortex (aPCX), a major afferent input to the LEC, by 3MO. The present results add to the growing evidence of AβPP-related hyper-excitability, and further implicate both soluble Aβ and non-Aβ AβPP metabolites in its early emergence.
authors.affiliation: Emotional Brain Institute, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA; Department of Child & Adolescent Psychiatry, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Wenjin
authors.initials: W
authors.lastname: Xu
authors.affiliation: Emotional Brain Institute, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA; Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA.
authors.forename: Shane
authors.initials: S
authors.lastname: Fitzgerald
authors.affiliation: Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA; Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA; Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Nixon
authors.affiliation: Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA; Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Efrat
authors.initials: E
authors.lastname: Levy
authors.affiliation: Emotional Brain Institute, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA; Department of Child & Adolescent Psychiatry, New York University School of Medicine, New York, NY 10016, USA; Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY 10016, USA. Electronic address: dwilson@nki.rfmh.org.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Wilson
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000367:Age Factors; D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D018728:Entorhinal Cortex / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D005071:Evoked Potentials / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009812:Odorants; D009833:Olfactory Pathways / Q000378:metabolism / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor
keywords: Alzheimer's disease; Amyloid-β; AβPP C-terminal fragments; AβPP metabolites; Lateral entorhinal cortex; Olfaction; Single-unit