RESUMEN
Alzheimer's disease (AD) poses an immense challenge in healthcare, lacking effective therapies. This study investigates the potential of anthranilamide derivative (AAD23), a selective M2 receptor antagonist, in proactively preventing cognitive impairments and cholinergic neuronal degeneration in G protein-coupled receptor kinase-5-deficient Swedish APP (GAP) mice. GAP mice manifest cognitive deficits by 7 months and develop senile plaques by 9 months. A 6-month AAD23 treatment was initiated at 5 months and stopped at 11 months before behavioral assessments without the treatment. AAD23-treated mice exhibited preserved cognitive abilities and improved cholinergic axonal health in the nucleus basalis of Meynert akin to wildtype mice. Conversely, vehicle-treated GAP mice displayed memory deficits and pronounced cholinergic axonal swellings in the nucleus basalis of Meynert. Notably, AAD23 treatment did not alter senile plaques and microgliosis. These findings highlight AAD23's efficacy in forestalling AD-related cognitive decline in G protein-coupled receptor kinase-5-deficient subjects, attributing its success to restoring cholinergic neuronal integrity and resilience, enhancing resistance against diverse degenerative insults.
Asunto(s)
Enfermedad de Alzheimer , Neuronas Colinérgicas , Disfunción Cognitiva , Quinasa 5 del Receptor Acoplado a Proteína-G , Ratones Transgénicos , Animales , Ratones , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/patología , Neuronas Colinérgicas/metabolismo , Neuronas Colinérgicas/efectos de los fármacos , Neuronas Colinérgicas/patología , Quinasa 5 del Receptor Acoplado a Proteína-G/metabolismo , Quinasa 5 del Receptor Acoplado a Proteína-G/genética , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Masculino , HumanosRESUMEN
The length of cholinergic or other neuronal axons in various brain regions are often correlated with the specific function of the region. Stereology is a useful method to quantify neuronal profiles of various brain structures. Here we provide a software-based stereology protocol to estimate the total length of cholinergic fibers in the nucleus basalis of Meynert (NBM) of the basal forebrain. The method uses a space ball probe for length estimates. The cholinergic fibers are visualized by choline acetyltransferase (ChAT) immunostaining with the horseradish peroxidase-diaminobenzidine (HRP-DAB) detection system. The staining protocol is also valid for fiber and cell number estimation in various brain regions using stereology software. The stereology protocol can be used for estimation of any linear profiles such as cholinoceptive fibers, dopaminergic/catecholaminergic fibers, serotonergic fibers, astrocyte processes, or even vascular profiles.
Asunto(s)
Núcleo Basal de Meynert/anatomía & histología , Fibras Colinérgicas/fisiología , Procesamiento de Imagen Asistido por Computador , Animales , Análisis de Datos , Masculino , Ratones Endogámicos C57BLRESUMEN
Sensitivity and reliability of animal behavioral assessment methods are critical for successful translation of in vitro findings to in vivo. Here we report a data transformation process in the elevated open platform task that generates a novel parameter, namely peak tolerance of fear (PTF) or its inversely correlated equivalent of anxiety quotient (AQ), to measure anxiogenic tendency in rodent. As compared to traditional parameters such as travel distance, time, or entries, PTF or AQ displays largely reduced data dispersion not only ingroup but also cross-study and cross-cohort, therefore representing a significant improvement of the methodology for rodent anxiety assessment.