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

Abstract

Background In recent years, mechanistic, epidemiologic, and interventional studies have indicated beneficial effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) against brain aging and age-related cognitive decline, with the most consistent effects against Alzheimer’s disease (AD) confined especially in the early or prodromal stages of the pathology. In the present study, we investigated the action of n-3 PUFA supplementation on behavioral performances and hippocampal neurogenesis, volume, and astrogliosis in aged mice subjected to a selective depletion of basal forebrain cholinergic neurons. Such a lesion represents a valuable model to mimic one of the most reliable hallmarks of early AD neuropathology. Methods Aged mice first underwent mu-p75-saporin immunotoxin intraventricular lesions to obtain a massive cholinergic depletion and then were orally supplemented with n-3 PUFA or olive oil (as isocaloric control) for 8 weeks. Four weeks after the beginning of the dietary supplementation, anxiety levels as well as mnesic, social, and depressive-like behaviors were evaluated. Subsequently, hippocampal morphological and biochemical analyses and n-3 PUFA brain quantification were carried out. Results The n-3 PUFA treatment regulated the anxiety alterations and reverted the novelty recognition memory impairment induced by the cholinergic depletion in aged mice. Moreover, n-3 PUFA preserved hippocampal volume, enhanced neurogenesis in the dentate gyrus, and reduced astrogliosis in the hippocampus. Brain levels of n-3 PUFA were positively related to mnesic abilities. Conclusions The demonstration that n-3 PUFA are able to counteract behavioral deficits and hippocampal neurodegeneration in cholinergically depleted aged mice promotes their use as a low-cost, safe nutraceutical tool to improve life quality at old age, even in the presence of first stages of AD.

Effects of Dietary n-3 LCPUFA Supplementation on the Hippocampus of Aging Female Mice: Impact on Memory, Lipid Raft-Associated Glutamatergic Receptors and Neuroinflammation

“…These cellular changes were associated with the amelioration of spatial and recognition memory skills in these animals [73]. Hippocampal astrogliosis was also reduced by a LCPUFA combination of DHA, EPA and n-3 docosapentaenoic acid (DPA) supplementation in aged male mice with forebrain cholinergic depletion, in correlation with recognition memory restoration [107]. The beneficial effect of n-3 LCPUFA in reverting the inflammatory scenario appears to be also achieved with specific individual n-3 LCPUFA species; thus, in a rat neuroinflammation model induced by central injection of IL-1β, EPA dietary supplementation ameliorated microglia and astrocytic activation in the hippocampus [108].…”

Cannabinoid Receptors and Glial Response Following a Basal Forebrain Cholinergic Lesion

“…Thus, animal models with a specific lesion of BFCNs are adequate for the study of dementia symptoms related with the prodromal stages of AD. The 192IgG-saporin lesion model in rat, first described in 1991, causes cognitive deficits in memory tasks such as the novel object recognition test, Morris water maze, and passive avoidance. , Consequently, it has been used in numerous studies as a model of memory impairment and neurodegeneration. − …”

Possible antidepressant mechanisms of omega-3 polyunsaturated fatty acids acting on the central nervous system

“…Omega-3 PUFAs play important roles in preventing neurodegeneration by inhibiting neuroinflammation, promoting synaptic plasticity and neurogenesis, facilitating nervous system repair, and protecting against the reduction of gray matter volume and the decline of white matter integrity ( 19 , 142 , 143 ). Studies have found that omega-3 PUFAs can promote the proliferation and migration of nerve cells, and inhibit apoptosis ( 48 , 144 ). According to a ten-year follow-up study, higher levels of plasma EPA and DHA are associated with a slower decline in medial temporal lobe volume and a lower risk of dementia in older adults ( 145 ).…”