Repeated multi-domain cognitive training prevents cognitive decline, anxiety and amyloid pathology found in a mouse model of Alzheimer disease

Abstract

Education, occupation, and an active lifestyle, comprising enhanced social, physical, and mental components are associated with improved cognitive functions in aged people and may delay the progression of various neurodegenerative diseases including Alzheimer’s disease. To investigate this protective effect, 3-month-old APPNL-G-F/NL-G-F mice were exposed to repeated single- or multi-domain cognitive training. Cognitive training was given at the age of 3, 6, & 9 months. Single-domain cognitive training was limited to a spatial navigation task. Multi-domain cognitive training consisted of a spatial navigation task, object recognition, and fear conditioning. At the age of 12 months, behavioral tests were completed for all groups. Then, mice were sacrificed, and their brains were assessed for pathology. APPNL-G-F/NL-G-F mice given multi-domain cognitive training compared to APPNL-G-F/NL-G-F control group showed an improvement in cognitive functions, reductions in amyloid load and microgliosis, and a preservation of cholinergic function. Additionally, multi-domain cognitive training improved anxiety in APPNL-G-F/NL-G-F mice as evidenced by measuring thigmotaxis behavior in the Morris water maze. There were mild reductions in microgliosis in the brain of APPNL-G-F/NL-G-F mice with single-domain cognitive training. These findings provide causal evidence for the potential of certain forms of cognitive training to mitigate the cognitive deficits in Alzheimer disease.

Experimental laboratory models as tools for understanding modifiable dementia risk

“…Consistent with its effects on learning and memory, cognitive training in the Morris water maze before the onset of pathology is reported to decrease Aβ plaque load, Aβ oligomers, and phosphorylated tau in 3xTg mice 91 . Similar beneficial effects of pre‐pathology multidomain cognitive training have been described, of greater magnitude than for water maze training alone 94 . For environmental enrichment, it is unclear whether improved cognition correlates with decreased dementia‐related pathology in transgenic AD models because increased, 102 unchanged, 103 or decreased 104 Aβ deposition in transgenic AD model mice subjected to enrichment compared to standard‐housed transgenic controls have been reported.…”

“… 89 Cognitive training is also used for cognitive stimulation; this can take the form of repeated exposure to the Morris water maze, 90 , 91 , 92 go‐no‐go task 93 or multiple tasks (water maze, novel object recognition, fear conditioning). 94 Environmental enrichment has diverse functional and structural impacts on the normal rodent brain, increasing neurogenesis, dendritic branching, dendritic spine numbers, synapse numbers, and synaptic plasticity ( 95 , 96 , reviewed in Ref. 97 ).…”

“… 91 Similar beneficial effects of pre‐pathology multidomain cognitive training have been described, of greater magnitude than for water maze training alone. 94 For environmental enrichment, it is unclear whether improved cognition correlates with decreased dementia‐related pathology in transgenic AD models because increased, 102 unchanged, 103 or decreased 104 Aβ deposition in transgenic AD model mice subjected to enrichment compared to standard‐housed transgenic controls have been reported. Divergent findings may be explained by differences in tissue sampling between studies, since brain regions differ in their sensitivity to Aβ deposition and the effects of environmental enrichment.…”

Cognitive Interventions: Symptomatic or Disease-Modifying Treatments in the Brain?

“…Notably, a study on individuals with MCI assessing the effects of a 9-month cognitive intervention alone (mindful awareness practice; MAP) on Aβ-42 levels (salivary sample) found no significant differences between the treatment arm (MAP) and the active control group (22). Even in preclinical AD models, evidence remains unclear, with some studies suggesting decreased (23)(24)(25), no change (26,27), or increased (28) Aβ load in transgenic mice exposed to cognitive stimulation (i.e., enriched environment or spatial training).…”