Abstract
BackgroundThe choice and appropriate use of animal models in drug discovery for Alzheimer’s disease (AD) is pivotal to successful clinical translation of novel therapeutics, yet true alignment of research is challenging. Current models do not fully recapitulate the human disease, and even exhibit various degrees of regional pathological burden and diverse functional alterations. Given this, relevant pathological and functional endpoints must be determined on a model-by-model basis. The present work explores the rTg4510 mouse model of tauopathy as a case study to define best practices for the selection and validation of cognitive and functional endpoints for the purposes of pre-clinical AD drug discovery.MethodsMale rTg4510 mice were first tested at an advanced age, 12 months, in multiple behavioural assays (step 1). Severe tau pathology and neurodegeneration was associated with profound locomotor hyperactivity and spatial memory deficits. Four of these assays were then selected for longitudinal assessment, from 4 to 12 months, to investigate whether behavioural performance changes as a function of accumulation of tau pathology (step 2). Experimental suppression of tau pathology—via doxycycline administration—was also investigated for its effect on functional performance.ResultsProgressive behavioural changes were detected where locomotor activity and rewarded alternation were found to most closely correlate with tau burden and neurodegeneration. Doxycycline initiated at 4 months led to a 50% suppression of transgene expression, which was sufficient to prevent subsequent increases in tau pathology and arrest related functional decline.ConclusionsThis two-step approach demonstrates the importance of selecting assays most sensitive to the phenotype of the model. A robust relationship was observed between pathological progression, development of phenotype, and their experimental manipulation—three crucial factors for assessing the translational relevance of future pre-clinical findings.
Highlights
The choice and appropriate use of animal models in drug discovery for Alzheimer’s disease (AD) is pivotal to successful clinical translation of novel therapeutics, yet true alignment of research is challenging
Study 1: Selection of cognitive and behavioural endpoints in 12- to 15-month-old male rTg4510 mice Missing and excluded data Four mice were excluded from the analysis of T-maze rewarded alternation data as these animals failed to complete a minimum of five trials
Severe tau pathology and brain atrophy in old male rTg4510 Bi-transgenic rTg4510 mice (CC) mice Widespread tau pathology was observed in coronal brain sections taken from 15-month-old male rTg4510 CC mice (Fig. 1a)
Summary
The choice and appropriate use of animal models in drug discovery for Alzheimer’s disease (AD) is pivotal to successful clinical translation of novel therapeutics, yet true alignment of research is challenging. The present work explores the rTg4510 mouse model of tauopathy as a case study to define best practices for the selection and validation of cognitive and functional endpoints for the purposes of pre-clinical AD drug discovery. AD drug discovery programmes have so far lacked late-stage clinical success [2, 3]. While some of these failures have arisen from incomplete understanding of drug properties or inappropriate study design [4, 5], many may reflect true negative effects. Pre-clinical validation forms an integral part of nearly every drug project, yet justification of disease model as well as the endpoint(s) chosen often appears ad hoc, or lacking. A major consideration for future AD pre-clinical efforts would be to better understand the benefits and limitations of existing behavioural and functional assays, their relationship with disease progression (e.g. [7]), and with clinical endpoints
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