Clock/Sleep-Dependent Learning and Memory in Male 3xTg-AD Mice at Advanced Disease Stages and Extrinsic Effects of Huprine X and the Novel Multitarget Agent AVCRI104P3.

Lydia Giménez-Llort,Maria Victòria Clos,Míriam Ratia,Belén Pérez,Albert Badia,Mikel Santana-Santana,Pelayo Camps,Diego Muñoz-Torrero

doi:10.3390/brainsci11040426

Lydia Giménez-Llort, Maria Victòria Clos + Show 6 more

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https://doi.org/10.3390/brainsci11040426

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Abstract

A new hypothesis highlights sleep-dependent learning/memory consolidation and regards the sleep-wake cycle as a modulator of β-amyloid and tau Alzheimer’s disease (AD) pathologies. Sundowning behavior is a common neuropsychiatric symptom (NPS) associated with dementia. Sleep fragmentation resulting from disturbances in sleep and circadian rhythms in AD may have important consequences on memory processes and exacerbate the other AD-NPS. The present work studied the effect of training time schedules on 12-month-old male 3xTg-AD mice modeling advanced disease stages. Their performance in two paradigms of the Morris water maze for spatial-reference and visual-perceptual learning and memory were found impaired at midday, after 4 h of non-active phase. In contrast, early-morning trained littermates, slowing down from their active phase, exhibited better performance and used goal-directed strategies and non-search navigation described for normal aging. The novel multitarget anticholinesterasic compound AVCRI104P3 (0.6 µmol·kg−1, 21 days i.p.) exerted stronger cognitive benefits than its in vitro equipotent dose of AChEI huprine X (0.12 μmol·kg−1, 21 days i.p.). Both compounds showed streamlined drug effectiveness, independently of the schedule. Their effects on anxiety-like behaviors were moderate. The results open a question of how time schedules modulate the capacity to respond to task demands and to assess/elucidate new drug effectiveness.

Highlights

The new hypothesis on the physiological function of sleep highlights sleep-depending learning and memory consolidation [1] and associated plasticity, as well as their strong implications on skill performance involved in many daily life activities [2]
Aβ levels [11], to the extent that it is regarded as a modulator of Alzheimer’s disease (AD) pathogenesis, while sleep disturbances are proposed as a predictor of dementia and Aβ pathology [12]
Schedule For increased accuracy of AVCRI104P3-treated in their search of 12-monththe firstthe time, the present study shows that the mice cognitive performance for the platform, as shown by the number of annulus crossings (Figure and theschedule, with old male 3xTg-AD mice in the Morris Water Maze (MWM) was sensitive to the training(2)

Summary

Introduction

The new hypothesis on the physiological function of sleep highlights sleep-depending learning and memory consolidation [1] and associated plasticity, as well as their strong implications on skill performance involved in many daily life activities [2]. Sleep deprivation increases the levels of tau and the spread of tau pathology [13]. These frequent sleep disturbances, with awakenings during the night and increased proclivity to sleep during daytime [14,15,16], are referred to as sundowning behavior, one of the most common co-morbid clinical manifestations associated with AD. Sleep fragmentation as a result of disturbances in sleep and circadian rhythms in AD may have important consequences on memory processes [5,17], but it may exacerbate the other neuropsychiatric symptoms (NPS)

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