Behavioral and psychological symptoms of dementia (BPSD) and impaired cognition reflect unsuccessful neuronal compensation in the pre-plaque stage and serve as early markers for Alzheimer’s disease in the APP23 mouse model

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HighlightsImpaired soft skills and cognition in APP23 model of pre-plaque Alzheimer’s disease.Deficits accompanied by unsuccessful neuronal compensation.Enriched Environment (EE) alleviates detected symptoms of Alzheimer’s disease.Observed symptoms can serve as early disease markers and EE as a therapy.Recent research on Alzheimer’s disease (AD) focuses on processes prior to amyloid-beta plaque deposition accounting for the progress of the disease. However, early mechanisms of AD are still poorly understood and predictors of the disease in the pre-plaque stage essential for initiating an early therapy are lacking. Behavioral and psychological symptoms of dementia (BPSD) and potentially impaired cognition may serve as predictors and early clinical diagnostic markers for AD. To investigate potential BPSD and cognitive impairments in association with neuronal cell development as such markers for AD in the pre-plaque stage, female APP23 mice at eight, 19 and 31 weeks of age and corresponding control animals were tested for BPSD (elevated zero maze; sucrose preference test), motor coordination (rotarod), spatial memory and reversal learning (Morris water maze) and hippocampal neurogenesis as a neuronal correlate for hippocampus-dependent behavior. To evaluate a potential therapeutic effect of physical, cognitive and social stimulation, animals were exposed to environmental enrichment (EE) for one, twelve or 24 weeks from five weeks of age. In APP23, decreased anxiety accompanied increased agitation from eight weeks of age. Impairment of spatial memory and learning flexibility prior to plaque deposition involved an insufficient use of spatial search strategies associated with an unsuccessful compensatory increase of neurogenesis. EE had an overall beneficial effect on behavior and neurogenesis and thus constitutes a therapeutic tool to slow disease progression. BPSD, cognition and associated impaired neurogenesis complement clinical diagnostic markers for pre-plaque AD and contribute to an early detection essential to halt disease progression.

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