Pathogenic tau species drive a psychosis-like phenotype in a mouse model of Alzheimer's disease

Koppel, Jeremy; Jimenez, Heidy; Azose, M.; d’Abramo, Cristina; Acker, Christopher M.; Buthorn, Justin J.; Greenwald, Blaine S.; Lewis, Jada; Lesser, Martin; Liu, Z.; Davies, Peter

doi:10.1016/j.bbr.2014.08.030

Cited by 18 publications

(31 citation statements)

References 61 publications

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“…In order to develop a preclinical mouse model of AD+P, we recently selected an AD model manifesting early frontal tauopathy, the transgenic rTg(tau P301L )4510 mouse, 110 and characterized PPI deficits over time in relationship to tau pathology. 111 We demonstrated that PPI deficits accrued over time in female rTg(tau P301L )4510 mice, and that these deficits were driven by the same pathogenic hyperphosphorylated tau molecules that we had previously observed in the frontal cortex of human female AD+P subjects. 100 This suggests that the rTg(tau P301L )4510 mouse may be a candidate for preclinical study of AD+P biology and the development of novel therapeutics.…”

Section: Future Directions: a Pathology-guided Approachsupporting

confidence: 70%

Optimal treatment of Alzheimer’s disease psychosis: challenges and solutions

Koppel¹,

Greenwald²

2014

NDT

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Psychotic symptoms emerging in the context of neurodegeneration as a consequence of Alzheimer’s disease was recognized and documented by Alois Alzheimer himself in his description of the first reported case of the disease. Over a quarter of a century ago, in the context of attempting to develop prognostic markers of disease progression, psychosis was identified as an independent predictor of a more-rapid cognitive decline. This finding has been subsequently well replicated, rendering psychotic symptoms an important area of exploration in clinical history taking – above and beyond treatment necessity – as their presence has prognostic significance. Further, there is now a rapidly accreting body of research that suggests that psychosis in Alzheimer’s disease (AD+P) is a heritable disease subtype that enjoys neuropathological specificity and localization. There is now hope that the elucidation of the neurobiology of the syndrome will pave the way to translational research eventuating in new treatments. To date, however, the primary treatments employed in alleviating the suffering caused by AD+P are the atypical antipsychotics. These agents are approved by the US Food and Drug Administration for the treatment of schizophrenia, but they have only marginal efficacy in treating AD+P and are associated with troubling levels of morbidity and mortality. For clinical approaches to AD+P to be optimized, this syndrome must be disentangled from other primary psychotic disorders, and recent scientific advances must be translated into disease-specific therapeutic interventions. Here we provide a review of atypical antipsychotic efficacy in AD+P, followed by an overview of critical neurobiological observations that point towards a frontal, tau-mediated model of disease, and we suggest a new preclinical animal model for future translational research.

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Section: Future Directions: a Pathology-guided Approachsupporting

confidence: 70%

Optimal treatment of Alzheimer’s disease psychosis: challenges and solutions

Koppel¹,

Greenwald²

2014

NDT

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“…One alternative is a mouse model containing a Tau mutation, P301L, associated with frontotemporal dementia. These mice have elevated p-Tau, and have recently been shown to have deficits in PPI that correlate with insoluble p-Tau levels (Koppel et al, 2014b). So called “triple transgenic” mouse models that in addition to APP and PSEN1 mutations contain the P301L mutation may thus represent a compelling model for future tests of the effects of kalirin reduction.…”

Section: Discussionmentioning

confidence: 99%

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

Krivinko

Erickson

Abrahamson

et al. 2017

Neurobiology of Aging

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Psychosis in Alzheimer 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 to 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 form of p21 protein (Cdc42/Rac)-activated kinases (PAKs), which function in signaling pathways for maintenance of dendritic spine density, morphology, and function.

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“…In our study, we observed that Tau58-2/B mice were more sensitive to an unexpected stimulus, as measured by a higher startle response in the Preyer reflex and touch escape assay. In two related P301S murine models it had been discovered that prepulse inhibition (PPI), another marker of sensorimotor gating, is altered (Koppel et al, 2014;Takeuchi et al, 2011). However, we were prevented from performing a PPI assay with our mice because of the motor weakness that characterizes the aged Tg animals.…”

Section: Discussionmentioning

confidence: 99%

Impulsivity, decreased social exploration, and executive dysfunction in a mouse model of frontotemporal dementia

Jeugd

Vermaercke

Halliday

et al. 2016

Neurobiology of Learning and Memory

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Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder, a major subset of which is characterized by the accumulation of abnormal forms of the protein tau, leading to impairments in motor functions as well as language and behavioral alterations. Tau58-2/B mice express human tau with the P301S mutation found in familial forms of FTLD in neurons. By assessing three age cohorts of Tau58-2/B mice in a comprehensive behavioral test battery, we found that the tauopathy animals showed age-dependent signs of impulsivity, decreased social exploration and executive dysfunction. The deficit in executive function was first limited to decreased spatial working memory, but with aging this was extended to impaired instrumental short-term memory. Tau pathology was prominent in brain regions underlying these behaviors. Thus, Tau-58-2/B mice recapitulate neurological deficits of the behavioral variant of frontotemporal dementia (bvFTD), presenting them as a suitable model to test therapeutic interventions for the amelioration of this variant.2 Keywords: Behavior; executive function; frontotemporal dementia; frontotemporal lobar degeneration; social exploration; tau Highlights• Tau58-2/B mice present with a tau pathology in cortical areas implicated in bvFTD.• Tau58-2/B mice exhibit motor and sensory gating anomalies at an early age.• With aging the mice show decreased sociability but no altered exploration.• The mice further display increased risk-taking behaviors and executive deficits.• First limited to spatial working memory, it later extends to instrumental memory.

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Pathogenic tau species drive a psychosis-like phenotype in a mouse model of Alzheimer's disease

Cited by 18 publications

References 61 publications

Optimal treatment of Alzheimer’s disease psychosis: challenges and solutions

Optimal treatment of Alzheimer’s disease psychosis: challenges and solutions

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

Impulsivity, decreased social exploration, and executive dysfunction in a mouse model of frontotemporal dementia

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Pathogenic tau species drive a psychosis-like phenotype in a mouse model of Alzheimer's disease

Cited by 18 publications

References 61 publications

Optimal treatment of Alzheimer&rsquo;s disease psychosis: challenges and solutions

Optimal treatment of Alzheimer&rsquo;s disease psychosis: challenges and solutions

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

Impulsivity, decreased social exploration, and executive dysfunction in a mouse model of frontotemporal dementia

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Optimal treatment of Alzheimer’s disease psychosis: challenges and solutions

Optimal treatment of Alzheimer’s disease psychosis: challenges and solutions