CD8+ T cells contribute to diet-induced memory deficits in aged male rats.

We have previously shown that short-term (3-day) high fat diet (HFD) consumption induces a neuroinflammatory response and subsequent impairment of long-term memory in aged, but not young adult, male rats. However, the immune cell phenotypes driving this proinflammatory response are not well understood. Previously, we showed that microglia isolated from young and aged rats fed a HFD express similar levels of priming and proinflammatory transcripts, suggesting that additional factors may drive the exaggerated neuroinflammatory response selectively observed in aged HFD-fed rats. It is established that T cells infiltrate both the young and especially the aged central nervous system (CNS) and contribute to immune surveillance of the parenchyma. Thus, we investigated the modulating role of short-term HFD on T cell presence in the CNS in aged rats using bulk RNA sequencing and flow cytometry. RNA sequencing results indicate that aging and HFD altered the expression of genes and signaling pathways associated with T cell signaling, immune cell trafficking, and neuroinflammation. Moreover, flow cytometry data showed that aging alone increased CD4+ and CD8+ T cell presence in the brain and that CD8+, but not CD4+, T cells were further increased in aged rats fed a HFD. Based on these data, we selectively depleted circulating CD8+ T cells via an intravenous injection of an anti-CD8 antibody in aged rats prior to 3 days of HFD to infer the functional role these cells may be playing in long-term memory and neuroinflammation. Results indicate that peripheral depletion of CD8+ T cells lowered hippocampal cytokine levels and prevented the HFD-induced i) increase in brain CD8+ T cells, ii) memory impairment, and iii) alterations in pre- and post-synaptic structures in the hippocampus and amygdala. Together, these data indicate a substantial role for CD8+ T cells in mediating diet-induced memory impairments in aged male rats.

Neurodegenerative Diseases: From Dysproteostasis, Altered Calcium Signalosome to Selective Neuronal Vulnerability to AAV-Mediated Gene Therapy.

Despite intense research into the multifaceted etiology of neurodegenerative diseases (ND), they remain incurable. Here we provide a brief overview of several major ND and explore novel therapeutic approaches. Although the cause (s) of ND are not fully understood, the accumulation of misfolded/aggregated proteins in the brain is a common pathological feature. This aggregation may initiate disruption of Ca++ signaling, which is an early pathological event leading to altered dendritic structure, neuronal dysfunction, and cell death. Presently, ND gene therapies remain unidimensional, elusive, and limited to modifying one pathological feature while ignoring others. Considering the complexity of signaling cascades in ND, we discuss emerging therapeutic concepts and suggest that deciphering the molecular mechanisms involved in dendritic pathology may broaden the phenotypic spectrum of ND treatment. An innovative multiplexed gene transfer strategy that employs silencing and/or over-expressing multiple effectors could preserve vulnerable neurons before they are lost. Such therapeutic approaches may extend brain health span and ameliorate burdensome chronic disease states.

Young adult and aged female rats are vulnerable to amygdala-dependent, but not hippocampus-dependent, memory impairment following short-term high-fat diet.

Global populations are increasingly consuming diets high in saturated fats and refined carbohydrates, and such diets have been well-associated with heightened inflammation and neurological dysfunction. Notably, older individuals are particularly vulnerable to the impact of unhealthy diet on cognition, even after a single meal, and pre-clinical rodent studies have demonstrated that short-term consumption of high-fat diet (HFD) induces marked increases in neuroinflammation and cognitive impairment. Unfortunately though, to date, most studies on the topic of nutrition and cognition, especially in aging, have been performed only in male rodents. This is especially concerning given that older females are more vulnerable to develop certain memory deficits and/or severe memory-related pathologies than males. Thus, the aim of the present study was to determine the extent to which short-term HFD consumption impacts memory function and neuroinflammation in female rats. Young adult (3 months) and aged (20-22 months) female rats were fed HFD for 3 days. Using contextual fear conditioning, we found that HFD had no effect on long-term contextual memory (hippocampus-dependent) at either age, but impaired long-term auditory-cued memory (amygdala-dependent) regardless of age. Gene expression of Il-1ß was markedly dysregulated in the amygdala, but not hippocampus, of both young and aged rats after 3 days of HFD. Interestingly, modulation of IL-1 signaling via central administration of the IL-1 receptor antagonist (which we have previously demonstrated to be protective in males) had no impact on memory function following the HFD in females. Investigation of the memory-associated gene Pacap and its receptor Pac1r revealed differential effects of HFD on their expression in the hippocampus and amygdala. Specifically, HFD induced increased expression of Pacap and Pac1r in the hippocampus, whereas decreased Pacap was observed in the amygdala. Collectively, these data suggest that both young adult and aged female rats are vulnerable to amygdala-dependent (but not hippocampus-dependent) memory impairments following short-term HFD consumption, and identify potential mechanisms related to IL-1ß and PACAP signaling in these differential effects. Notably, these findings are strikingly different than those previously reported in male rats using the same diet regimen and behavioral paradigms, and highlight the importance of examining potential sex differences in the context of neuroimmune-associated cognitive dysfunction.

Dietary fatty acids differentially impact phagocytosis, inflammatory gene expression, and mitochondrial respiration in microglial and neuronal cell models.

The consumption of diets high in saturated fatty acids and/or refined carbohydrates are associated with neuroinflammation, cognitive dysfunction, and neurodegenerative disease. In contrast, diets high in polyunsaturated fatty acids are associated with anti-inflammatory and neuroprotective effects. We have previously shown that high fat diet (HFD) consumption increases saturated fatty acids and decreases polyunsaturated fatty acids in the hippocampus. We have further shown that HFD elicits exaggerated neuroinflammation and reduced synaptic elements, and results in robust memory deficits in aged rats. Here, we examined the impact of palmitate, an abundant dietary saturated fat, on a variety of cellular responses in BV2 microglia and HippoE-14 neurons, and the extent to which the omega-3 fatty acid, docosahexaenoic acid (DHA), would buffer against these responses. Our data demonstrate that DHA pretreatment prevents or partially attenuates palmitate-induced alterations in proinflammatory, endoplasmic reticulum stress, and mitochondrial damage-associated gene expression in both cell types. Furthermore, we show that synaptoneurosomes isolated from aged, HFD-fed mice are engulfed by BV2 microglia at a faster rate than synaptoneurosomes isolated from aged, chow-fed mice, suggesting HFD alters signaling at synapses to hasten their engulfment by microglia. Consistent with this notion, we found modest increases in complement proteins and a decrease in CD47 protein expression on synaptoneurosomes isolated from the hippocampus of aged, HFD-fed mice. Interestingly, palmitate reduced BV2 microglial phagocytosis, but only of synaptoneurosomes isolated from chow-fed mice, an effect that was prevented by DHA pretreatment. Lastly, we measured the impact of palmitate and DHA on mitochondrial function in both microglial and neuronal cell models using the Seahorse XFe96 Analyzer. These data indicate that DHA pretreatment does not mitigate palmitate-induced reductions in mitochondrial respiration in BV2 microglia and HippoE-14 neurons, suggesting DHA may be acting downstream of mitochondrial function to exert its protective effects. Together, this study provides evidence that DHA can ameliorate the negative impact of palmitate on a variety of cellular functions in microglia- and neuron-like cells.