Kalirin reduction rescues psychosis-associated behavioral deficits in APPswe/PSEN1dE9 transgenic mice.
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.
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Josh M
JM
Krivinko
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Susan L
SL
Erickson
Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Eric E
EE
Abrahamson
Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Zachary P
ZP
Wills
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.
Milos D
MD
Ikonomovic
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.
Peter
P
Penzes
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.
Robert A
RA
Sweet
D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics / Q000523:psychology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D003071:Cognition; D049229:Dendritic Spines; D004195:Disease Models, Animal; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency* / Q000502:physiology*; D006801:Humans; D001523:Mental Disorders / Q000150:complications / Q000235:genetics* / Q000523:psychology; D008822:Mice, Transgenic; D010766:Phosphorylation; D053764:Presenilin-1 / Q000235:genetics; D011618:Psychotic Disorders / Q000150:complications / Q000235:genetics* / Q000523:psychology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D065852:Spatial Memory; D054462:p21-Activated Kinases / Q000378:metabolism / Q000502:physiology
D016564:Amyloid beta-Protein Precursor; D020662:Guanine Nucleotide Exchange Factors; C548820:KALRN protein, mouse; D053764:Presenilin-1; C580804:presenilin 1, mouse; C486708:Pak7 protein, mouse; D054462:p21-Activated Kinases
Alzheimer disease; Kalirin; Psychosis