Neuroprotective Role of Dietary Supplementation with Omega-3 Fatty Acids in the Presence of Basal Forebrain Cholinergic Neurons Degeneration in Aged Mice

Abstract

As major components of neuronal membranes, omega-3 polyunsaturated fatty acids (n-3 PUFA) exhibit a wide range of regulatory functions. Recent human and animal studies indicate that n-3 PUFA may exert beneficial effects on aging processes. Here we analyzed the neuroprotective influence of n-3 PUFA supplementation on behavioral deficits, hippocampal neurogenesis, volume loss, and astrogliosis in aged mice that underwent a selective depletion of basal forebrain cholinergic neurons. Such a lesion represents a valid model to mimic a key component of the cognitive deficits associated with dementia. Aged mice were supplemented with n-3 PUFA or olive oil (as isocaloric control) for 8 weeks and then cholinergically depleted with mu-p75-saporin immunotoxin. Two weeks after lesioning, mice were behaviorally tested to assess anxious, motivational, social, mnesic, and depressive-like behaviors. Subsequently, morphological and biochemical analyses were performed. In lesioned aged mice the n-3 PUFA pre-treatment preserved explorative skills and associative retention memory, enhanced neurogenesis in the dentate gyrus, and reduced volume and VAChT levels loss as well as astrogliosis in hippocampus. The present findings demonstrating that n-3 PUFA supplementation before cholinergic depletion can counteract behavioral deficits and hippocampal neurodegeneration in aged mice advance a low-cost, non-invasive preventive tool to enhance life quality during aging.

Behavioral, neuromorphological, and neurobiochemical effects induced by omega-3 fatty acids following basal forebrain cholinergic depletion in aged mice

“…As for morphological and biochemical correlates, the cholinergic lesion increased hippocampal astrogliosis in agreement with similar findings in cholinergically depleted adult rats [107,124] and aged mice [56], as well as in AD patients [125]. In the present study, we did not find any effect of the immunotoxic cholinergic lesion on hippocampal neurogenesis, in line with previous research in adult [126] and aged [56] mice. Hippocampal volumes were not significantly affected by the cholinergic lesion.…”

“…Moreover, AD brains are additionally characterized by a prominent reactive astrogliosis due to the progressive neurodegeneration [ 156 ]. In this study, while the hippocampal astrogliosis was detrimentally enhanced by the cholinergic depletion, the n-3 PUFA supplementation exerted a neuroprotective and anti-inflammatory role by lowering the increased astrogliosis hippocampal levels, in line with previous studies in aged subjects [ 29 , 56 , 63 , 157 ]. However, we cannot exclude the involvement of microglia and oligodendroglia [ 158 , 159 ] in modulating the n-3 PUFA effects on saporin lesions.…”

“…In our study, the n-3 PUFA stimulation of neuronal progenitor proliferation (i.e., BrdU + and SOX2 + cells) in the DG occurred after both sham and saporin lesions in aged mice, but the increase in neuronal differentiation of newborn neurons (i.e., DCX + cells) persisted only after the immunotoxic lesion, probably to compensate for the cholinergic neuronal loss. Similar neurogenic effects of n-3 PUFA have been reported also in one of our previous studies [ 56 ], in which n-3 PUFA supplementation was administered in aged mice before cholinergic depletion. Notably, in case of traumatic brain injury [ 134 , 135 ] and cerebral ischemia [ 136 , 137 ], hippocampal neurogenesis is stimulated in order to recruit compensatory neural networks and to preserve the functions affected by the lesion.…”

“…The n-3 PUFA efficacy in counteracting the age-related brain atrophy has been previously well-documented in rodent [ 28 , 63 , 64 ] and human [ 130 – 133 ] investigations. A preventive n-3 PUFA action against hippocampal neuronal loss has been already observed in aged mice when the n-3 PUFA administration preceded the cholinergic depletion [ 56 ]. Such an action may be attributed to n-3 PUFA positive influence in helping neurons to cope with aging by potentiating synaptogenesis and reducing apoptosis and glial degeneration [ 29 , 56 , 63 ].…”

“…injection of the mu-p75-saporin (saporin) immunotoxin is a valid animal model to partially mimic early AD pathology in mice, since the loss of integrity of the basal forebrain cholinergic system is one of the most reliable hallmarks of AD pathology [53]. Namely, the saporin immunotoxin provokes a selective and permanent removal of basal forebrain cholinergic inputs to the hippocampus, the entire cortical mantle, the amygdala, and the olfactory bulb [54][55][56].…”