title: Sensory network dysfunction, behavioral impairments, and their reversibility in an Alzheimer's β-amyloidosis mouse model.
abstract: The unique vulnerability of the olfactory system to Alzheimer's disease (AD) provides a quintessential translational tool for understanding mechanisms of synaptic dysfunction and pathological progression in the disease. Using the Tg2576 mouse model of β-amyloidosis, we show that aberrant, hyperactive olfactory network activity begins early in life, before detectable behavioral impairments or comparable hippocampal dysfunction and at a time when amyloid-β (Aβ) deposition is restricted to the olfactory bulb (OB). Hyperactive odor-evoked activity in the piriform cortex (PCX) and increased OB-PCX functional connectivity emerged at a time coinciding with olfactory behavior impairments. This hyperactive activity persisted until later in life when the network converted to a hyporesponsive state. This conversion was Aβ-dependent, because liver-X receptor agonist treatment to promote Aβ degradation rescued the hyporesponsive state and olfactory behavior. These data lend evidence to a novel working model of olfactory dysfunction in AD and, complimentary to other recent works, suggest that disease-relevant network dysfunction is highly dynamic and region specific, yet with lasting effects on cognition and behavior.
authors: Emotional Brain Institute, Nathan S Kline Institute for Psychiatric Research, Orangeburg, New York 10962, USA. dww53@case.edu
authors: Daniel W
authors: DW
authors: Wesson
authors: Anne H
authors: AH
authors: Borkowski
authors: Gary E
authors: GE
authors: Landreth
authors: Ralph A
authors: RA
authors: Nixon
authors: Efrat
authors: E
authors: Levy
authors: Donald A
authors: DA
authors: Wilson
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000686:Amyloidosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001526:Behavioral Symptoms / Q000209:etiology* / Q000235:genetics; D001565:Benzoates / Q000494:pharmacology; D052160:Benzothiazoles; D001596:Benzylamines / Q000494:pharmacology; D058256:Brain Waves / Q000235:genetics / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D004569:Electroencephalography; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005583:Fourier Analysis; D006185:Habituation, Psychophysiologic / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009812:Odorants; D009833:Olfactory Pathways / Q000473:pathology; D012678:Sensation Disorders / Q000209:etiology* / Q000235:genetics; D012903:Smell / Q000235:genetics / Q000502:physiology; D013844:Thiazoles / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001565:Benzoates; D052160:Benzothiazoles; D001596:Benzylamines; C473027:GW 3965; D013844:Thiazoles; C009462:thioflavin T