Voluntary Running and Environmental Enrichment Restores Impaired Hippocampal Neurogenesis in a Triple Transgenic Mouse Model of Alzheimers Disease

Abstract

Alzheimer's disease (AD) affects memory and neurogenesis. Adult neurogenesis plays an important role in memory function and impaired neurogenesis contributes to cognitive deficits associated with AD. Increased physical/ cognitive activity is associated with both reduced risk of dementia and increased neurogenesis. Previous attempts to restore hippocampal neurogenesis in transgenic mice by voluntary running (RUN) and environmental enrichment (ENR) provided controversial results due to lack of non-transgenic (non-Tg) control and inclusion of social isolation as "standard" housing environment. Here, we determine the effect of RUN and ENR upon hippocampal neurogenesis in a triple transgenic (3xTg-AD) mouse model of AD, which mimics AD pathology in humans. We used single and double immunohistochemistry to determine the area density of hippocampal proliferating cells, measured by the presence of phosphorylated Histone H3 (HH3), and their potential neuronal and glial phenotype by co-localizing the proliferating cells with the immature neuronal marker doublecortin (DCX), mature neuronal marker (NeuN) and specific astroglial marker (GFAP). Our results show that 3xTg-AD mice in control environment exhibit impaired hippocampal neurogenesis compared to non-Tg animals at 9 months of age. Exposure to RUN and ENR housing restores hippocampal neurogenesis in 3xTg-AD animals to non-Tg control levels. Differentiation into neurones and glial cells is affected neither by transgenic status nor by housing environment. These results suggest that hippocampus of 3xTg-AD animals maintains the potential for cellular plasticity. Increase in physical activity and/or cognitive experience enhances neurogenesis and provides a potential for stimulation of cognitive function in AD.

Prolonged Running, not Fluoxetine Treatment, Increases Neurogenesis, but does not Alter Neuropathology, in the 3xTg Mouse Model of Alzheimer’s Disease

“…Outside of the traditional markers of AD neuropathology, 6 months of wheel running was further shown to reduce markers of oxidative stress in the brains of 7-month-old 3xTg mice and to protect these mice against an age-related loss of synaptic integrity (García-Mesa et al 2011). A separate study showed that voluntary running increased neurogenesis when evaluated at 9 months of age; running, however, did not change the fate of the newborn cell phenotypes, which agrees with our current results in the same 3xTg mice (Rodriguez et al 2011) but not with our previous study in younger C57Bl6 mice (Marlatt et al 2010). …”

Exercise as a pro-cognitive, pro-neurogenic and anti-inflammatory intervention in transgenic mouse models of Alzheimer’s disease

“…Training of 24 month old Tg-NSE/hPS-2 mice on a treadmill for three months was found to reduce hippocampal A␤42 protein and tau phosphorylation as well as improve performance of the mice in the MWM (Koo et al, 2013;Um et al, 2011). A number of other studies also provide evidence for exerciseinduced amelioration of cognitive function in mice in which AD pathology is deemed to be advanced but disappointingly have not included any data on exercise-induced alterations on typical AD pathologies (Marlatt et al, 2013;Rodriguez et al, 2011).…”

How to make a hippocampal dentate gyrus granule neuron

“…These changes have been linked to depletion in the neural progenitor pool, owing to reduced Notch signaling, and an increase in astrogliogenesis at the expense of producing neurons (Lugert et al, 2010;Encinas et al, 2011). Finally, hippocampal neurogenesis deficits have been linked to cognitive defects characteristic of depression (Patricio et al, 2013), impairment in early Alzheimer's disease pathology (Demars et al, 2010;Faure et al, 2011;Mu and Gage, 2011;Rodriguez et al, 2011), bipolar disorder (Valvezan and Klein, 2012;Walton et al, 2012) and schizophrenia (SCZD) (Tamminga et al, 2010;Walton et al, 2012;Hagihara et al, 2013). More specifically, alterations in DG granule neuron maturation have been implicated in the etiology and pathogenesis of schizophrenia and bipolar disorder (see Box 1; Reif et al, 2006;Yamasaki et al, 2008;Walton et al, 2012;Hagihara et al, 2013;Shin et al, 2013).…”