The impact of pimavanserin on psychotic phenotypes and tau phosphorylation in the P301L/COMT– and rTg(P301L)4510 mouse models of Alzheimer's disease
Abstract Introduction Psychosis in Alzheimer's disease (AD) is associated with grave clinical consequences including a precipitous cognitive decline and a hastened demise. These outcomes are aggravated by use of existing antipsychotic medications, which are also associated with cognitive declin...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-01-01
|
| Series: | Alzheimer’s & Dementia: Translational Research & Clinical Interventions |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/trc2.12247 |
| _version_ | 1826950793934143488 |
|---|---|
| author | Heidy Jimenez Leslie Adrien Adam Wolin John Eun Eric H. Chang Ethan S. Burstein Jesus Gomar Peter Davies Jeremy Koppel |
| author_facet | Heidy Jimenez Leslie Adrien Adam Wolin John Eun Eric H. Chang Ethan S. Burstein Jesus Gomar Peter Davies Jeremy Koppel |
| author_sort | Heidy Jimenez |
| collection | DOAJ |
| description | Abstract Introduction Psychosis in Alzheimer's disease (AD) is associated with grave clinical consequences including a precipitous cognitive decline and a hastened demise. These outcomes are aggravated by use of existing antipsychotic medications, which are also associated with cognitive decline and increased mortality; preclinical models that would develop new therapeutic approaches are desperately needed. The current report evaluates the ability of the neoteric antipsychotic, pimavanserin, to normalize hyperkinesis and sensorimotor gating in the novel catechol‐O‐methyltransferase (COMT) deleted P301L/COMT– and rTg(P301L)4510 models of psychotic AD, and the impact of pimavanserin on tau pathology. Methods Female P301L/COMT– mice were behaviorally characterized for abnormalities of locomotion and sensorimotor gating, and biochemically characterized for patterns of tau phosphorylation relative to relevant controls utilizing high‐sensitivity tau enzyme‐linked immunosorbent assay (ELISA). Female P301L/COMT– and rTg(P301L)4510 mice were randomized to pimavanserin or vehicle treatment to study the ability of pimavanserin to normalize locomotion and rescue sensorimotor gating. Additionally, high‐sensitivity tau ELISA was used to investigate the impact of treatment on tau phosphorylation. Results P301L/COMT– mice evidenced a hyperlocomotive phenotype and deficits of sensorimotor gating relative to wild‐type mice on the same background, and increased tau phosphorylation relative to COMT‐competent P301L mice. Pimavanserin normalized the hyperkinetic phenotype in both the P301L/COMT– and rTg(P301L)4510 mice but had no impact on sensorimotor gating in either model. Pimavanserin treatment had little impact on tau phosphorylation patterns. Discussion These data suggest that pimavanserin ameliorates tau‐driven excessive locomotion. Given the morbidity associated with aberrant motor behaviors such as pacing in AD and lack of effective treatments, future studies of the impact of pimavanserin on actigraphy in patients with this syndrome may be warranted. |
| first_indexed | 2024-04-10T21:53:36Z |
| format | Article |
| id | doaj.art-aa55218e025343b18f73ff0eae412e85 |
| institution | Directory Open Access Journal |
| issn | 2352-8737 |
| language | English |
| last_indexed | 2025-02-17T22:37:25Z |
| publishDate | 2022-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Alzheimer’s & Dementia: Translational Research & Clinical Interventions |
| spelling | doaj.art-aa55218e025343b18f73ff0eae412e852024-12-03T12:37:31ZengWileyAlzheimer’s & Dementia: Translational Research & Clinical Interventions2352-87372022-01-0181n/an/a10.1002/trc2.12247The impact of pimavanserin on psychotic phenotypes and tau phosphorylation in the P301L/COMT– and rTg(P301L)4510 mouse models of Alzheimer's diseaseHeidy Jimenez0Leslie Adrien1Adam Wolin2John Eun3Eric H. Chang4Ethan S. Burstein5Jesus Gomar6Peter Davies7Jeremy Koppel8Northwell Health The Feinstein Institutes for Medical Research Manhasset New York USANorthwell Health The Feinstein Institutes for Medical Research Manhasset New York USANorthwell Health The Feinstein Institutes for Medical Research Manhasset New York USANorthwell Health The Feinstein Institutes for Medical Research Manhasset New York USANorthwell Health The Feinstein Institutes for Medical Research Manhasset New York USAACADIA Pharmaceuticals San Diego California USANorthwell Health The Feinstein Institutes for Medical Research Manhasset New York USANorthwell Health The Feinstein Institutes for Medical Research Manhasset New York USANorthwell Health The Feinstein Institutes for Medical Research Manhasset New York USAAbstract Introduction Psychosis in Alzheimer's disease (AD) is associated with grave clinical consequences including a precipitous cognitive decline and a hastened demise. These outcomes are aggravated by use of existing antipsychotic medications, which are also associated with cognitive decline and increased mortality; preclinical models that would develop new therapeutic approaches are desperately needed. The current report evaluates the ability of the neoteric antipsychotic, pimavanserin, to normalize hyperkinesis and sensorimotor gating in the novel catechol‐O‐methyltransferase (COMT) deleted P301L/COMT– and rTg(P301L)4510 models of psychotic AD, and the impact of pimavanserin on tau pathology. Methods Female P301L/COMT– mice were behaviorally characterized for abnormalities of locomotion and sensorimotor gating, and biochemically characterized for patterns of tau phosphorylation relative to relevant controls utilizing high‐sensitivity tau enzyme‐linked immunosorbent assay (ELISA). Female P301L/COMT– and rTg(P301L)4510 mice were randomized to pimavanserin or vehicle treatment to study the ability of pimavanserin to normalize locomotion and rescue sensorimotor gating. Additionally, high‐sensitivity tau ELISA was used to investigate the impact of treatment on tau phosphorylation. Results P301L/COMT– mice evidenced a hyperlocomotive phenotype and deficits of sensorimotor gating relative to wild‐type mice on the same background, and increased tau phosphorylation relative to COMT‐competent P301L mice. Pimavanserin normalized the hyperkinetic phenotype in both the P301L/COMT– and rTg(P301L)4510 mice but had no impact on sensorimotor gating in either model. Pimavanserin treatment had little impact on tau phosphorylation patterns. Discussion These data suggest that pimavanserin ameliorates tau‐driven excessive locomotion. Given the morbidity associated with aberrant motor behaviors such as pacing in AD and lack of effective treatments, future studies of the impact of pimavanserin on actigraphy in patients with this syndrome may be warranted.https://doi.org/10.1002/trc2.12247Alzheimer's diseaseantipsychoticdopaminelocomotionprepulse inhibitionpsychosis |
| spellingShingle | Heidy Jimenez Leslie Adrien Adam Wolin John Eun Eric H. Chang Ethan S. Burstein Jesus Gomar Peter Davies Jeremy Koppel The impact of pimavanserin on psychotic phenotypes and tau phosphorylation in the P301L/COMT– and rTg(P301L)4510 mouse models of Alzheimer's disease Alzheimer’s & Dementia: Translational Research & Clinical Interventions Alzheimer's disease antipsychotic dopamine locomotion prepulse inhibition psychosis |
| title | The impact of pimavanserin on psychotic phenotypes and tau phosphorylation in the P301L/COMT– and rTg(P301L)4510 mouse models of Alzheimer's disease |
| title_full | The impact of pimavanserin on psychotic phenotypes and tau phosphorylation in the P301L/COMT– and rTg(P301L)4510 mouse models of Alzheimer's disease |
| title_fullStr | The impact of pimavanserin on psychotic phenotypes and tau phosphorylation in the P301L/COMT– and rTg(P301L)4510 mouse models of Alzheimer's disease |
| title_full_unstemmed | The impact of pimavanserin on psychotic phenotypes and tau phosphorylation in the P301L/COMT– and rTg(P301L)4510 mouse models of Alzheimer's disease |
| title_short | The impact of pimavanserin on psychotic phenotypes and tau phosphorylation in the P301L/COMT– and rTg(P301L)4510 mouse models of Alzheimer's disease |
| title_sort | impact of pimavanserin on psychotic phenotypes and tau phosphorylation in the p301l comt and rtg p301l 4510 mouse models of alzheimer s disease |
| topic | Alzheimer's disease antipsychotic dopamine locomotion prepulse inhibition psychosis |
| url | https://doi.org/10.1002/trc2.12247 |
| work_keys_str_mv | AT heidyjimenez theimpactofpimavanserinonpsychoticphenotypesandtauphosphorylationinthep301lcomtandrtgp301l4510mousemodelsofalzheimersdisease AT leslieadrien theimpactofpimavanserinonpsychoticphenotypesandtauphosphorylationinthep301lcomtandrtgp301l4510mousemodelsofalzheimersdisease AT adamwolin theimpactofpimavanserinonpsychoticphenotypesandtauphosphorylationinthep301lcomtandrtgp301l4510mousemodelsofalzheimersdisease AT johneun theimpactofpimavanserinonpsychoticphenotypesandtauphosphorylationinthep301lcomtandrtgp301l4510mousemodelsofalzheimersdisease AT erichchang theimpactofpimavanserinonpsychoticphenotypesandtauphosphorylationinthep301lcomtandrtgp301l4510mousemodelsofalzheimersdisease AT ethansburstein theimpactofpimavanserinonpsychoticphenotypesandtauphosphorylationinthep301lcomtandrtgp301l4510mousemodelsofalzheimersdisease AT jesusgomar theimpactofpimavanserinonpsychoticphenotypesandtauphosphorylationinthep301lcomtandrtgp301l4510mousemodelsofalzheimersdisease AT peterdavies theimpactofpimavanserinonpsychoticphenotypesandtauphosphorylationinthep301lcomtandrtgp301l4510mousemodelsofalzheimersdisease AT jeremykoppel theimpactofpimavanserinonpsychoticphenotypesandtauphosphorylationinthep301lcomtandrtgp301l4510mousemodelsofalzheimersdisease AT heidyjimenez impactofpimavanserinonpsychoticphenotypesandtauphosphorylationinthep301lcomtandrtgp301l4510mousemodelsofalzheimersdisease AT leslieadrien impactofpimavanserinonpsychoticphenotypesandtauphosphorylationinthep301lcomtandrtgp301l4510mousemodelsofalzheimersdisease AT adamwolin impactofpimavanserinonpsychoticphenotypesandtauphosphorylationinthep301lcomtandrtgp301l4510mousemodelsofalzheimersdisease AT johneun impactofpimavanserinonpsychoticphenotypesandtauphosphorylationinthep301lcomtandrtgp301l4510mousemodelsofalzheimersdisease AT erichchang impactofpimavanserinonpsychoticphenotypesandtauphosphorylationinthep301lcomtandrtgp301l4510mousemodelsofalzheimersdisease AT ethansburstein impactofpimavanserinonpsychoticphenotypesandtauphosphorylationinthep301lcomtandrtgp301l4510mousemodelsofalzheimersdisease AT jesusgomar impactofpimavanserinonpsychoticphenotypesandtauphosphorylationinthep301lcomtandrtgp301l4510mousemodelsofalzheimersdisease AT peterdavies impactofpimavanserinonpsychoticphenotypesandtauphosphorylationinthep301lcomtandrtgp301l4510mousemodelsofalzheimersdisease AT jeremykoppel impactofpimavanserinonpsychoticphenotypesandtauphosphorylationinthep301lcomtandrtgp301l4510mousemodelsofalzheimersdisease |