Is the Effect of Glucose on Hippocampal Memory Insulin-Dependent?

Insulin is now established as a key regulator of brain mechanisms that include both glucose metabolism and synaptic plasticity, especially within the hippocampus. However, the complex set of signaling cascades mediating these effects is not yet understood. Recent studies, many from our lab, have established that insulin plays multiple roles in the brain: in addition to regulation of energy supply, metabolism, and feeding, our work has shown that hippocampal insulin is a key modulator of learning and memory. Exogneous insulin enhances, while pharmacological blockade of intrahippocampal insulin impairs, both metabolism and cognition. Moreover, when systemic insulin signalling is impaired, such as in Type 2 diabetes, hippocampal function and metabolism are again impaired. Memory processes both in the hippocampus and elsewhere (e.g. amygdala) are well established to be sensitive to glucose supply: performance on memory tasks is limited by glucose availability, and provision of additional glucose supports enhanced task performance. Systemically, insulin regulates glucose transport from the blood into cells; conversely, glucose regulates insulin synthesis and release from the pancreas, so that the two molecules mutually regulate. Although this relationship between insulin and glucose has been well studied, there has been little work on their interaction in the brain. For instance, although we have shown that insulin regulates hippocampal glucose metabolism, it is unknown whether glucose acts to enhance memory via stimulation of insulin release within the hippocampus, or whether insulin\u27s procognitive effects are via stimulation of glucose metabolism or a direct modulation of plasticity. In this study, Glut4, an insulin-dependent glucose transporter found on some hippocampal neurons, was directly blocked. Indinavir, a Glut4 inhibitor, was injected directly into the dorsal hippocampus of rats in the presence or absence of a peritoneal glucose injection in order to assess changes in cognition. It was found that indinavir treatment significantly impaired cognition in spontaneous alternation tasks, reduced anxiety, and, surprisingly, and had no effect on cognitive performance in a novel object recognition task. These data support a novel role for GluT4 as a mediator of hippocampal memory processing and suggest that insulin acts to regulate cognitive function at least in part via GluT4-mediated glucose transport into neurons. In the presence of indinavir, glucose was unable to enhance memory, consistent with this interpretation and suggesting that enhancement of hippocampal memory by glucose may require hippocampal insulin signaling. Post-mortem molecular studies of hippocampal protein expression provided further insight into the molecular impact of both glucose treatment and GluT4 blockade

Apoptotic dysregulation mediates stem cell competition and tissue regeneration

Abstract Since adult stem cells are responsible for replenishing tissues throughout life, it is vital to understand how failure to undergo apoptosis can dictate stem cell behavior both intrinsically and non-autonomously. Here, we report that depletion of pro-apoptotic Bax protein bestows hair follicle stem cells with the capacity to eliminate viable neighboring cells by sequestration of TNFα in their membrane. This in turn induces apoptosis in “loser” cells in a contact-dependent manner. Examining the underlying mechanism, we find that Bax loss-of-function competitive phenotype is mediated by the intrinsic activation of NFκB. Notably, winner stem cells differentially respond to TNFα, owing to their elevated expression of TNFR2. Finally, we report that in vivo depletion of Bax results in an increased stem cell pool, accelerating wound-repair and de novo hair follicle regeneration. Collectively, we establish a mechanism of mammalian cell competition, which can have broad therapeutic implications for tissue regeneration and tumorigenesis

Thy1 marks a distinct population of slow-cycling stem cells in the mouse epidermis

Abstract The presence of distinct stem cells that maintain the interfollicular epidermis is highly debated. Here, we report a population of keratinocytes, marked by Thy1, in the basal layer of the interfollicular epidermis. We find that epidermal cells expressing differential levels of Thy1 display distinct transcriptional signatures. Thy1+ keratinocytes do not express T cell markers, express a unique transcriptional profile, cycle significantly slower than basal epidermal progenitors and display significant expansion potential in vitro. Multicolor lineage tracing analyses and mathematical modeling reveal that Thy1+ basal keratinocytes do not compete neutrally alike interfollicular progenitors and contribute long-term to both epidermal replenishment and wound repair. Importantly, ablation of Thy1+ cells strongly impairs these processes, thus indicating the non-redundant function of Thy1+ stem cells in the epidermis. Collectively, these results reveal a distinct stem cell population that plays a critical role in epidermal homeostasis and repair

Altered ubiquitin signaling induces Alzheimer’s disease-like hallmarks in a three-dimensional human neural cell culture model

Abstract Alzheimer’s disease (AD) is characterized by toxic protein accumulation in the brain. Ubiquitination is essential for protein clearance in cells, making altered ubiquitin signaling crucial in AD development. A defective variant, ubiquitin B + 1 (UBB+1), created by a non-hereditary RNA frameshift mutation, is found in all AD patient brains post-mortem. We now detect UBB+1 in human brains during early AD stages. Our study employs a 3D neural culture platform derived from human neural progenitors, demonstrating that UBB+1 alone induces extracellular amyloid-β (Aβ) deposits and insoluble hyperphosphorylated tau aggregates. UBB+1 competes with ubiquitin for binding to the deubiquitinating enzyme UCHL1, leading to elevated levels of amyloid precursor protein (APP), secreted Aβ peptides, and Aβ build-up. Crucially, silencing UBB+1 expression impedes the emergence of AD hallmarks in this model system. Our findings highlight the significance of ubiquitin signalling as a variable contributing to AD pathology and present a nonclinical platform for testing potential therapeutics