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Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide classically implicated in the regulation of energy homeostasis, sleep–wake cycle and motivated behaviors. Over the last 30 years, an increasing amount of evidence has revealed a complex, non-linear role in memory processing. In this mini-review, we summarize experimental findings on the multifaceted influence of MCH on memory, highlighting how this neuropeptide can promote consolidation by improving synaptic efficacy, induce the forgetting of hippocampus-dependent memories during REM sleep or negatively regulate memory formation. We also discuss emerging evidence linking MCH dysregulation to the pathophysiology of Alzheimer’s disease (AD). Early interest in MCH as a cerebrospinal fluid biomarker has been superseded by non-invasive blood assays. Recent data, however, suggest therapeutic potential and a unique pathological vulnerability. While emerging evidence suggests MCH somata may show early resilience, their axonal projections are severely compromised by amyloid pathology. Ultimately, tau pathology appears to drive late-stage somatic degeneration and reduced activation during REM sleep. Importantly, activating surviving MCH neurons has been shown to restore sleep architecture in preclinical models, offering a potential therapeutic target for sleep disturbances. In conclusion, decades of basic memory research together with human and preclinical studies identify the MCH system as an important neuromodulatory network for understanding the memory and sleep alterations characteristic of AD.

The streptozotocin (STZ) experimental model of sporadic Alzheimer’s disease (SAD), the most prevalent form of this type of dementia, has become a valuable tool to study the behavioral and morphological changes that occur during the gradual development of this pathology. We used the STZ experimental model in combination with the novel object recognition test (NORT) and immunohistochemical techniques to evaluate the recognition memory decline and morphological alterations in memory-related structures (hippocampus and cortex). Our analysis included five different time points after intracerebroventricular (ICV) administration of 3 mg/kg of STZ or artificial cerebrospinal fluid (aCSF) as a control. The time points included three distinct stages: early (15 and 30 days), intermediate (60 days), and late (90 and 120 days). We found that recognition memory impairment started in the intermediate stage and persisted through the later stages. Morphologically, we detected significant astrogliosis starting in the early stages, whereas cholinergic changes began in the intermediate stage. No neuronal loss was observed at any of the time points analyzed. Our results further support the hypothesis that astrogliosis constitutes an initial pathological event that may compromise the hippocampal cholinergic system and can contribute to the onset of recognition memory deficits.

Mitochondrial respiratory complexes are organized into supercomplexes (SC) to regulate electron flow and mitigate oxidative stress. Alterations in SC organization in the brain may affect energy expenditure, oxidative stress, and neuronal survival. In this report, we investigated the amount, activity and organization of mitochondrial complex I (CI) in the hippocampus of 12‐month‐old McGill‐R‐Thy1‐APP transgenic (Tg) rats, an animal model of Alzheimer's‐like cerebral amyloidosis. By means of BN‐PAGE, we found that the organization of SC did not differ between genotypes, but a lower abundance of SC was detected in Tg compared to wild‐type (WT) rats. Using a more sensitive technique (2‐D electrophoresis followed by Western blot), higher levels of free CI and a decrease in the relative abundance of assembled CI in SC (I‐III ₂ and I‐III ₂ ‐IV) were observed in Tg rats. In‐gel activity assays showed that the total activity of CI (CI + SC‐CI) is lower in Tg compared to WT, while Tg samples show a significant decrease in SC‐CI‐associated activity. This alteration in CI assembly was associated with nitro‐oxidative stress and changes in mitochondrial fusion‐fission parameters. To assess CI composition, we applied LC–MS/MS to the isolated CI from BN‐PAGE and found that 11 of 45 subunits described in mammals were found to be less abundant in Tg. We examined the levels of the nuclear‐derived NDUFA9 subunit, which is critical for CI assembly, and found higher levels in the cytoplasmic fraction and lower levels in the mitochondrial fraction in Tg, suggesting that brain amyloidosis affects the import of CI subunits from the cytosol to the mitochondria, destabilizing the SC. This is the first report to characterize the types, abundance and activity of SC in the hippocampus of an animal model of cerebral amyloidosis, providing additional experimental evidence for the molecular mechanisms underlying the brain bioenergetic deficit characteristic of Alzheimer's disease. image

Background/Objectives: Alzheimer’s disease (AD), a leading cause of dementia, lacks effective long-term treatments. Current therapies offer temporary relief or fail to halt its progression and are often inaccessible due to cost. AD involves multiple pathological processes, including amyloid beta (Aβ) deposition, insulin resistance, tau protein hyperphosphorylation, and systemic inflammation accelerated by gut microbiota dysbiosis originating from a leaky gut. Given this context, exploring alternative therapeutic interventions capable of addressing the multifaceted components of AD etiology is essential. Methods: This study suggests D-Pinitol (DPIN) as a potential treatment modifier for AD. DPIN, derived from carob pods, demonstrates insulin-sensitizing, tau hyperphosphorylation inhibition, and antioxidant properties. To test this hypothesis, we studied whether chronic oral administration of DPIN (200 mg/kg/day) could reverse the AD-like disease progression in the 5×FAD mice. Results: Results showed that treatment of 5×FAD mice with DPIN improved cognition, reduced hippocampal Aβ and hyperphosphorylated tau levels, increased insulin-degrading enzyme (IDE) expression, enhanced pro-cognitive hormone circulation (such as ghrelin and leptin), and normalized the PI3K/Akt insulin pathway. This enhancement may be mediated through the modulation of cyclin-dependent kinase 5 (CDK5). DPIN also protected the gut barrier and microbiota, reducing the pro-inflammatory impact of the leaky gut observed in 5×FAD mice. DPIN reduced bacterial lipopolysaccharide (LPS) and LPS-associated inflammation, as well as restored intestinal proteins such as Claudin-3. This effect was associated with a modulation of gut microbiota towards a more balanced bacterial composition. Conclusions: These findings underscore DPIN’s promise in mitigating cognitive decline in the early AD stages, positioning it as a potential disease modifier.

This work aims to clarify the effect of dietary polyunsaturated fatty acid (PUFA) intake on the adult brain affected by amyloid pathology. McGill-R-Thy1-APP transgenic (Tg) rat and 5xFAD Tg mouse models that represent earlier or later disease stages were employed. The animals were exposed to a control diet (CD) or an HFD based on corn oil, from young (rats) or adult (mice) ages for 24 or 10 weeks, respectively. In rats and mice, the HFD impaired reference memory in wild-type (WT) animals but did not worsen it in Tg, did not cause obesity, and did not increase triglycerides or glucose levels. Conversely, the HFD promoted stronger microglial activation in Tg vs. WT rats but had no effect on cerebral amyloid deposition. IFN-γ, IL-1β, and IL-6 plasma levels were increased in Tg rats, regardless of diet, while CXCL1 chemokine levels were increased in HFD-fed mice, regardless of genotype. Hippocampal 3-nitrotyrosine levels tended to increase in HFD-fed Tg rats but not in mice. Overall, an HFD with an elevated omega-6-to-omega-3 ratio as compared to the CD (25:1 vs. 8.4:1) did not aggravate the outcome of AD regardless of the stage of amyloid pathology, suggesting that many neurobiological processes relevant to AD are not directly dependent on PUFA intake.

All fields of medicine have had to change and adapt in response to the COVID-19 pandemic. In this respect, frail and immunocompromised patients have been particularly affected. Such patients are commonly treated in oncology, a field that has witnessed a revolution in its protocols, as physicians and institutions address this new situation. This paper details the aspects of oncology that have been affected by the pandemic, in areas such as chemotherapy, surgery and radiotherapy, together with the sharp rise in the use of telemedicine. Some of these changes will probably be permanent and may even come to be seen as a positive outcome of the pandemic.

Nucleoredoxin (Nrx) belongs to the Thioredoxin protein family and functions in redox-mediated signal transduction. It contains the dithiol active site motif Cys-Pro-Pro-Cys and interacts and regulates different proteins in distinct cellular pathways. Nrx was shown to be catalytically active in the insulin assay and recent findings indicate that Nrx functions, in fact, as oxidase. Here, we have analyzed Nrx in the mammalian retina exposed to (perinatal) hypoxia-ischemia/reoxygenation, combining ex vivo and in vitro models. Our data show that Nrx regulates cell differentiation, which is important to (i) increase the number of glial cells and (ii) replenish neurons that are lost following the hypoxic insult. Nrx is essential to maintain cell morphology. These regulatory changes are related to VEGF but do not seem to be linked to the Wnt/β-catenin pathway, which is not affected by Nrx knock-down. In conclusion, our results strongly suggest that hypoxia-ischemia could lead to alterations in the organization of the retina, related to changes in RPE cell differentiation. Nrx may play an essential role in the maintenance of the RPE cell differentiation state via the regulation of VEGF release.

Rare coding variants in TREM2, PLCG2, and ABI3 were recently associated with the susceptibility to Alzheimer’s disease (AD) in Caucasians. Frequencies and AD-associated effects of variants differ across ethnicities. To start filling the gap on AD genetics in South America and assess the impact of these variants across ethnicity, we studied these variants in Argentinian population in association with ancestry. TREM2 (rs143332484 and rs75932628), PLCG2 (rs72824905), and ABI3 (rs616338) were genotyped in 419 AD cases and 486 controls. Meta-analysis with European population was performed. Ancestry was estimated from genome-wide genotyping results. All variants show similar frequencies and odds ratios to those previously reported. Their association with AD reach statistical significance by meta-analysis. Although the Argentinian population is an admixture, variant carriers presented mainly Caucasian ancestry. Rare coding variants in TREM2, PLCG2, and ABI3 also modulate susceptibility to AD in populations from Argentina, and they may have a European heritage.