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Neurobiol Aging. 2017 Jun;54:59-70. doi: 10.1016/j.neurobiolaging.2017.02.006. Epub 2017 Feb 16.

Kalirin reduction rescues psychosis-associated behavioral deficits in APPswe/PSEN1dE9 transgenic mice.

Author information

1
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
2
Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
3
Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
4
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Geriatric Research, Education, and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA.
5
Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
6
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Mental Illness Research, Education, and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA. Electronic address: sweetra@upmc.edu.

Abstract

Psychosis in Alzheimer's disease (AD+P) represents a distinct clinical and neurobiological AD phenotype and is associated with more rapid cognitive decline, higher rates of abnormal behaviors, and increased caregiver burden compared with AD without psychosis. On a molecular level, AD+P is associated with greater reductions in the protein kalirin, a guanine exchange factor which has also been linked to the psychotic disease, schizophrenia. In this study, we sought to determine the molecular and behavioral consequences of kalirin reduction in APPswe/PSEN1dE9 mice. We evaluated mice with and without kalirin reduction during tasks measuring psychosis-associated behaviors and spatial memory. We found that kalirin reduction in APPswe/PSEN1dE9 mice significantly attenuated psychosis-associated behavior at 12 months of age without changing spatial memory performance. The 12-month-old APPswe/PSEN1dE9 mice with reduced kalirin levels also had increased levels of the active, phosphorylated forms of p21 protein (Cdc42/Rac)-activated kinases (PAKs), which function in signaling pathways for maintenance of dendritic spine density, morphology, and function.

KEYWORDS:

Alzheimer disease; Kalirin; Psychosis

[Indexed for MEDLINE]
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