title: Pathogenic tau species drive a psychosis-like phenotype in a mouse model of Alzheimer's disease.
abstract: Psychotic Alzheimer's disease (AD+P) is a rapidly progressive variant of AD associated with an increased burden of frontal tau pathology that affects up to 50% of those with AD, and is observed more commonly in females. To date, there are no safe and effective medication interventions with an indication for treatment in this condition, and there has been only very limited exploration of potential animal models for pre-clinical drug development. Pathogenic tau is over represented in the frontal cortex in AD+P, especially in females. In order to develop a candidate animal model of AD+P, we employed a tau mouse model with a heavy burden of frontal tau pathology, the rTg(tauP301L)4510 mouse, hereafter termed rTg4510. We explored deficits of prepulse inhibition of acoustic startle (PPI), a model of psychosis in rodents, and the correlation between pathogenic phospho-tau species associated with AD+P and PPI deficits in female mice. We found that female rTg4510 mice exhibit increasing PPI deficits relative to littermate controls from 4.5 to 5.5 months of age, and that these deficits are driven by insoluble fractions of the phospho-tau species pSer396/404, pSer202, and pThr231 found to be associated with human AD+P. This preliminary data suggests the utility of the rTg4510 mouse as a candidate disease model of human female AD+P. Further work expanded to include both genders and other behavioral outcome measures relevant to AD+P is necessary.
authors.affiliation: The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA. Electronic address: jkoppel@nshs.edu.
authors.forename: J
authors.initials: J
authors.lastname: Koppel
authors.affiliation: The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA.
authors.forename: H
authors.initials: H
authors.lastname: Jimenez
authors.affiliation: Touro College, Brooklyn, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Azose
authors.affiliation: The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA.
authors.forename: C
authors.initials: C
authors.lastname: D'Abramo
authors.affiliation: The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA.
authors.forename: C
authors.initials: C
authors.lastname: Acker
authors.affiliation: The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA.
authors.forename: J
authors.initials: J
authors.lastname: Buthorn
authors.affiliation: The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA.
authors.forename: B S
authors.initials: BS
authors.lastname: Greenwald
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lewis
authors.affiliation: The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA.
authors.forename: M
authors.initials: M
authors.lastname: Lesser
authors.affiliation: Hofstra University, Hempstead, LI, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.affiliation: The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA.
authors.forename: P
authors.initials: P
authors.lastname: Davies
mesh_terms: D000161:Acoustic Stimulation; D000367:Age Factors; D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007266:Inhibition, Psychological; D007930:Leucine / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011392:Proline / Q000235:genetics; D011618:Psychotic Disorders / Q000150:complications* / Q000235:genetics*; D013216:Reflex, Startle / Q000235:genetics / Q000502:physiology; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D016875:tau Proteins; D011392:Proline; D007930:Leucine
keywords: Acoustic Startle; Alzheimer's disease; Prepulse inhibition; Psychosis; Tangle; Tau