Early Ultrasonic Vocalization Deficits and Related Thyroarytenoid Muscle Pathology in the Transgenic TgF344-AD Rat Model of Alzheimer's Disease

Background: Alzheimer's disease (AD) is a progressive neurologic disease and the most common cause of dementia. Classic pathology in AD is characterized by inflammation, abnormal presence of tau protein, and aggregation of β-amyloid that disrupt normal neuronal function and lead to cell death. Deficits in communication also occur during disease progression and significantly reduce health, well-being, and quality of life. Because clinical diagnosis occurs in the mid-stage of the disease, characterizing the prodrome and early stages in humans is currently challenging. To overcome these challenges, we use the validated (F344-Tg(Prp-APP, Prp-PS1)19/Rrrc) transgenic rat model that manifests cognitive, behavioral, and neuropathological dysfunction akin to AD in humans.

Objectives: The overarching goal of our work is to test the central hypothesis that pathology and related behavioral deficits such as communication dysfunction in part manifest in the peripheral nervous system and corresponding target tissues already in the early stages. The primary aims of this study are to test the hypotheses that: (1) changes in ultrasonic vocalizations (USV) occur in the prodromal stage at 6 months of age and worsen at 9 months of age, (2) inflammation as well as AD-related pathology can be found in the thyroarytenoid muscle (TA) at 12 months of age (experimental endpoint tissue harvest), and to (3) demonstrate that the rat model is an appropriate model for preclinical investigations of early AD-related vocal deficits.

Methods: USVs were collected from male ( = 19) and wildtype (WT) rats ( = 19) at 6 months ( = 38; WT:  = 19; :  = 19) and 9 months of age ( = 18; WT:  = 10; :  = 8) and acoustically analyzed for duration, mean power, principal frequency, low frequency, high frequency, peak frequency, and call type. RT-qPCR was used to assay peripheral inflammation and AD-related pathology via gene expressions in the TA muscle of male rats ( = 6) and WT rats ( = 6) at 12 months of age.

Results: This study revealed a significant reduction in mean power of ultrasonic calls from 6 to 9 months of age and increased peak frequency levels over time in rats compared to WT controls. Additionally, significant downregulation of AD-related genes , , , and as well as downregulation of pro-inflammatory gene was found in the TA muscle of rats at 12 months of age.

Discussion: Our findings demonstrate early and progressive vocal deficits in the rat model. We further provide evidence of dysregulation of AD-pathology-related genes as well as inflammatory genes in the TA muscles of rats in the early stage of the disease, confirming this rat model for early-stage investigations of voice deficits and related pathology.