Post-traumatic stress disorder (PTSD) is associated with dysfunction of the hypothalamo-pituitary-adrenocortical (HPA) axis, accompanied by alterations in immune function, microbiota composition, and brain regions, including the hippocampus. CRHR2 receptor agonists, urocortin 2 (UCN2) and urocortin 3 (UCN3), regulate stress-related neuroendocrine activity. The present study aimed to investigate how a single intranasal administration of UCN2 or UCN3 modulates bacterial composition and inflammatory activity in the spleen/isolated splenocytes and alters the expression of neuroinflammatory and neurogenic markers in the dorsal (dHipp) and ventral hippocampus (vHipp) in male rats exposed to single prolonged stress (SPS) model of PTSD. SPS increased Enterobacteriaceae 16S rRNA levels and slightly reduced Lactobacillus abundance, while both urocortins prevented these effects. In the spleen, SPS suppressed expression of immune cell function markers, whereas UCN3 mitigated these effects. In isolated splenocytes stimulated ex vivo with lipopolysaccharide, UCN2 and UCN3 restored the reduced mRNA expression of proinflammatory markers, including IL-1β, IL-12p40, NOS, and CD69. Alterations in inflammatory markers correlated with Enterobacteriaceae and Lactobacillus. In the brain, SPS-induced changes were observed primarily in the vHipp, where expression of neuroinflammatory markers, including Iba1, TREM2, and CX3CR1, were decreased and restored by urocortin treatment. Conversely, SPS increased DCX mRNA levels, whereas UCN2 and UCN3 reduced them. Neuroinflammatory markers in the vHipp correlated with splenic microbiota and inflammatory markers. Overall, these findings suggest that CRHR2 stimulation by intranasal UCN2/UCN3 administration prevents PTSD-induced alterations through interconnected effects on splenic microbiota composition, peripheral immune responses, and hippocampal synaptic plasticity and neuroinflammatory markers.
Neuropeptides (NPs) are small peptides, produced and secreted by neurons, serving as neuromodulators and chemical messengers that influence neuronal growth, proliferation, and differentiation. Despite their diverse and important roles, the discovery and functional characterization of many NPs remain incomplete. This study aimed to extract and identify novel NPs from rat brain tissue. For this purpose, NPs were purified using gel filtration chromatography and sequenced by mass spectrometry (MS). After characterization, one candidate peptide (NP1) was selected for functional evaluation in primary rat hippocampal neurons. NP1-induced changes were assessed through morphological analysis and protein expression measurements using Western blot and ELISA. Our results revealed that NP treatment markedly enhanced neurite outgrowth and increased neuronal differentiation rate in primary hippocampal cultures compared to the untreated control group. Immunofluorescence analyses showed that NP1 localizes to both the cytoplasm and nucleus of neurons, suggesting its involvement in multiple cellular processes, including signaling, gene regulation, and structural functions. SPR analysis further demonstrated that NP exhibits strong DNA-binding affinity, supporting its potential involvement in transcriptional regulation during neuronal development. Expression analysis confirmed that NP upregulated Cyclin D1, a key regulator of neuronal differentiation, without affecting BAF53A expression. Moreover, NP treatment elevated BDNF and Tau expression levels while reducing SHH expression, suggesting a BDNF-Tau-dependent mechanism. Our results suggest that the characterized NP and its homologs may play roles in neural growth-related disorders such as Rett syndrome, Fragile X syndrome, Down syndrome, and autism spectrum disorder that need further investigation.
Activation of periventricular and hypothalamic substance P (SP) (NK1) receptors triggers the classical defence (stress) reaction but inhibits the hypothalamic-pituitary-adrenal (HPA) axis. The mechanisms of the HPA axis inhibition by SP are not clearly understood. This study in rats was designed to investigate the effect of stress and intracerebroventricular (ICV) SP injection on serotonin (5-HT) neurotransmission in the raphe nuclei and the hypothalamus. Immobilisation stress increased ACTH release, accelerated 5-HT turnover in the dorsal raphe nucleus (DRN) and in individual hypothalamic nuclei, but not in the paraventricular nucleus (PVN). ICV SP injection (500 pmol) produced a strong stress response, however, ACTH concentrations in plasma did not increase. SP accelerated 5-HT utilisation in the DRN but did not alter 5-HT synthesis and its degradation to 5-hydroxyindolacetic acid (5-HIAA) in the hypothalamic nuclei examined; minor changes were observed in the dorsomedial nucleus (DMN). A microdialysis study in conscious rats showed a drop in 5-HT release in the PVN (- 42%, P < 0.05) and DMN (- 56%, P < 0.01) compared to the values detected prior to ICV injection of SP. We demonstrate that activation of periventricular SP receptors considerably enhances 5-HT metabolism in the DRN, but not in the hypothalamic nuclei, the terminal projection field of the nucleus. Our data indicate that the decline in 5-HT release in the PVN and DMN, which indicates a rapid decrease in 5-HT neurotransmission, may represent an important mechanism in preventing the rise in ACTH following ICV SP.
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, with a five-year survival rate of 6%, yet the underlying causes remain poorly understood. The neuropeptide galanin (GAL) and its three receptors (GAL1-3-R) are known to modulate tumor biology. This study characterizes the expression patterns of the GAL system in healthy and diseased pancreas to evaluate its potential as a biomarker for disease progression. Immunohistochemical staining for GAL and GAL1-3-R was performed on tissue samples from healthy controls (n = 10), pancreatitis (n = 10), and PDAC (n = 34). Immunoreactive scores were quantified across histological compartments and were correlated with TNM stage, perineural invasion, and Union for International Cancer Control classification. GAL was widely expressed, with significant upregulation in lobular ducts and nerve bundles of PDAC compared to controls. Intra-neural GAL expression in PDAC positively correlated with advanced nodal stages and perineural invasion. In pancreatitis, GAL1-R expression was selectively increased in lobular ducts. Although GAL2-R expression peaked in endocrine cells, intra-neural GAL2-R was significantly downregulated in PDAC compared to healthy tissue, with further decreases in advanced stages. GAL3-R was predominantly localized to ducts and acini, showing higher expression in PDAC endocrine compartments than in pancreatitis or healthy tissue. Our findings demonstrate significant remodeling of the galaninergic system during pancreatic inflammation and carcinogenesis. Stage-dependent intra-neural GAL increases correlate with nodal involvement and perineural invasion, suggesting its potential as a prognostic biomarker for tumor aggressiveness. Progressive intra-neural GAL2-R loss in PDAC may limit receptor-agonist therapy efficacy, necessitating receptor-status screening for personalized patient stratification in future clinical applications.
Mitochondrial biogenesis is essential for maintaining energy homeostasis and chondrocyte function in articular cartilage, and its impairment contributes to cartilage degeneration and osteoarthritis pathogenesis. PACAP (pituitary adenylate cyclase-activating polypeptide) has recently emerged as a regulator of cellular metabolism, but its role in chondrocyte mitochondrial biology remains unclear. In this study, we investigated whether PACAP38 promotes mitochondrial biogenesis in rat primary chondrocytes. Cells were treated with PACAP38 (50 or 100 nM) for 48 h. PACAP38 enhanced mitochondrial function in a dose-dependent manner, as evidenced by increased complex I activity, maximal oxygen consumption rate (OCR), and ATP production. PACAP38 also increased the mtDNA/nDNA ratio and the protein expression of mitochondrial complex subunits NDUFB8 and MTCO2, indicating enhanced mitochondrial biogenesis. MitoTracker red staining further revealed that PACAP38 significantly increased mitochondrial mass. Mechanistically, PACAP38 upregulated the expression of Nrf1 and TFAM, two key transcription factors for mitochondrial biogenesis, at both mRNA and protein levels. Moreover, PACAP38 increased SIRT1 expression and decreased acetylated PGC-1α levels. Notably, shRNA-mediated silencing of either SIRT1 or its downstream target PGC-1α abolished the upregulation of Nrf1 and TFAM, the increase in mitochondrial mass, and the enhancement of ATP production. Collectively, these findings demonstrate that PACAP38 promotes mitochondrial biogenesis in rat primary chondrocytes through the SIRT1/PGC-1α signaling pathway, suggesting a potential therapeutic target for cartilage degenerative diseases.
Galanin receptor 2 (GALR2), as a subtype of neuropeptide galanin receptor, is predominantly expressed in the central and peripheral nervous systems. Accumulating evidence suggests that GALR2 is involved in the pathogenesis of depression, Alzheimer's disease, epilepsy, neuropathic pain, multiple sclerosis, as well as in neurological tumors. Here, we summarize the current knowledge on the molecular architecture, signal transduction mechanisms, and diverse biological functions of GALR2. In addition, we also discuss the involvement of GALR2 in neurological diseases, with a particular emphasis on evaluating its potential as a novel and viable therapeutic target for future drug development.
Neuropeptide Y (NPY) and galanin (GAL), two of the most abundant neuropeptides in the mammalian nervous system, are consistently associated with brain disorders, yet their therapeutic potential remains unrealized. Both are state-dependent modulators that are released under physiological load, acting as adaptive circuit stabilizers. Both have generated expensive drug programs that failed, not because the biology was wrong, but because the development strategy was. This manuscript uses NPY and GAL as paired case studies to argue that inconsistent translation reflects strategy mismatch in target selection, modality, dosing logic, and endpoint design, rather than weak targets. We synthesize molecular organization, structural biology, circuit function and human genetic evidence, and dissect clinical failures. We close with a concrete, indication-anchored development roadmap to maximize NPY and GAL drug development potential.
The investigation of the functional roles of peptide signalling represents an important route to understanding evolution of specific physiological traits and behaviours in metazoans. Allatostatins and their cognate receptors are classically defined as invertebrate neuropeptide hormones. Accumulating evidence recognises allatostatin C as a conserved signalling molecule across all invertebrate lineages, with reported functions spanning from regulation of feeding and digestion to immune responses and modulation of core nociception. Their orthologues across phyla imply biological functions of wider evolutionary significance. In particular, the presumed relationship with the somatostatin/opioid signalling receptors, modulating pain in mammals, warrants consideration. Here we combined in silico and experimental approaches to describe the molecular determinants of the allatostatin C signalling in the cephalopod Octopus vulgaris. This organism has been pivotal in understanding complex neurobiology due to the evolution of a large centralised nervous system. Our investigation resolved a single prepropeptide encompassing allatostatin C peptide (OvAstC) and two distinct allatostatin C receptors (OvAstCR1 and OvAstCR2). The single predicted mature peptide (AVITACYFQAVSCY) was shown to differentially activate the two identified cognate receptors. PCR analysis carried out in O. vulgaris tissues showed a broad distribution of OvAstC and OvAstCRs. This wide expression, while including nervous tissues, clearly extends to the immune and digestive systems. This distribution is consistent with a pleiotropic role of this peptidergic system. The neuro-sensory expression and the reinforced opioid/somatostatin-related phylogenetic placement of OvAstC/OvAstCRs, encourage further physiological investigation of the neuromodulatory control of sensory processing, including nociception in cephalopods.
The mesolimbic dopamine (DA) system is a central regulator of reward processing, motivation, and affective state. Neuropeptide Y (NPY), one of the most abundant neuropeptides in the brain, is highly expressed within the nucleus accumbens (NAc), a key node of the mesolimbic pathway. Although NPY signaling has been implicated in stress resilience, affective behavior, and reward processing, its mechanistic influence on accumbal DA transmission remains poorly defined. Here, we examined receptor-specific NPY modulation of DA release within the NAc core using fast-scan cyclic voltammetry (FSCV) in acute mouse brain slices. Bath application of NPY significantly increased evoked DA release in female but not male mice. The selective Y1 receptor agonist [Leu31,Pro34]NPY similarly enhanced DA release in females, and these effects were abolished by the Y1 receptor antagonist BIBO 3304, confirming Y1 receptor specificity. In contrast, Y1 receptor agonists had no significant effect on DA release in males, whereas Y1 receptor antagonism led to an increase in DA release. Complementary experiments demonstrated that antagonism of Y5 receptors with L-152,804 increased DA release in both sexes. These data highlight NPY receptors as potent modulators of NAc core dopamine function and provide mechanistic insight to how NPY signaling could serve as a critical interface linking stress, affective state, and DA-dependent behaviors.
Violence and aggression arise from dynamic interactions among genetic liability, neurobiological regulation, and environmental stressors, mediated by a distributed "core aggression circuit" encompassing the prefrontal cortex, amygdala, hypothalamus, and brainstem. Neuropeptide Y (NPY), a highly conserved 36-amino acid neuromodulator, has emerged as a key stress-buffering and emotion-regulatory agent with relevance to impulsive and reactive aggression. This review synthesizes translational evidence linking NPY biology to aggression and violence by integrating molecular mechanisms, receptor pharmacology, neural circuitry, and clinical phenotypes across psychiatric disorders. Evidence from animal models, neuroimaging, cerebrospinal fluid and plasma studies, and genetic investigations indicates that reduced central NPY signaling is generally associated with heightened stress sensitivity and impulsivity, well recognized risk factors for aggression, and, in paradigms using direct aggression measures, with aggressive behavior itself, whereas preserved or elevated NPY supports resilience. Mechanistically, postsynaptic Y1 receptor signaling dampens excitability in corticolimbic and amygdalahypothalamic pathways and restrains stress-driven autonomic/endocrine escalation via modulation of hypothalamic corticotropin-releasing hormone and hypothalamic-pituitary-adrenal-axis activity. In contrast, presynaptic Y2 receptor limits NPY availability and, when overactivated, may promote vulnerability to anxiety and emotional dysregulation. Genetic variants and disorder-linked alterations further support clinical relevance, with indirect implications for intermittent explosive disorder, borderline personality disorder, oppositional defiant disorder, and disruptive mood dysregulation disorder. Despite inconsistent study designs and limited aggressionspecific clinical data, NPY represents a candidate biomarker and potential therapeutic target for stress-related conditions involving aggression, though most therapeutic findings remain preclinical or disorder-general, underscoring the need for aggression-focused clinical trials, dimensional refinement of anger/aggression constructs, and cautious translational framing.
The Apelin-13/APJ system exerts anti-excitatory, antioxidant, and anti-inflammatory effects in the central nervous system, however, its influence on seizure-associated pathological high-frequency oscillations (HFOs) and concurrent neuroinflammatory tissue injury has not been investigated in vivo. This study evaluated the effects of intracerebroventricular Apelin-13 pretreatment on seizure severity, cortical electrophysiology, and neuroinflammatory injury in a pentylenetetrazol (PTZ)-induced acute rat epilepsy model. Thirty adult male Wistar rats were assigned to three groups (n = 10): Control, PTZ (70 mg/kg, i.p.), and APL + PTZ (Apelin-13 3 μg/5 μl, i.c.v., 15 min prior to PTZ). Seizure severity was scored using the Racine scale. Cortical EEG was recorded via epidural electrodes and analyzed by power spectral density across six bands. Brain sections were evaluated by haematoxylin-eosin staining, TUNEL assay, and eNOS/VEGF immunohistochemistry. Apelin-13 significantly reduced seizure severity (p < 0.05). PTZ elevated cortical power across all frequency bands. Apelin-13 attenuated power in the theta, alpha, gamma, and HFO bands (p < 0.05 to p < 0.01), with the strongest suppression in the HFO band (p < 0.01), where APL + PTZ values were indistinguishable from controls. Apelin-13 reduced the neuronal damage score (p < 0.01), apoptotic index (p < 0.05), eNOS expression (p < 0.01), and VEGF expression (p < 0.001). These findings indicate that Apelin-13 suppresses seizure-associated HFO activity and attenuates convergent nitrosative, apoptotic, and vascular injury pathways in acute PTZ-induced epilepsy, supporting the Apelin-13/APJ axis as a mechanistically distinct neuroprotective candidate warranting further translational investigation.
Spinal cord injury (SCI) is characterized by primary mechanical trauma and subsequent secondary pathogenic cascades, with chronic neuroinflammation impeding neurological functional recovery. Microglial activation, mitochondrial dysfunction, and mitophagy are key pathological players, while the role of triggering receptor expressed on myeloid cells 1 (TREM1) in SCI remains incompletely elucidated. This study explored TREM1 targeting and the regulation of microglial mitophagy in SCI using 8-week-old female C57BL/6 J mice and BV2 microglial cells. Mice were administered the TREM1 inhibitor LP17 or physiological saline. Assessments included behavioral evaluations, Nissl staining, immunofluorescence staining, Western blot analysis, and transmission electron microscopy. We found that TREM1 expression peaked at 3 days post-SCI and was specifically localized to microglia. LP17 inhibited TREM1 expression, improved 4-week post-injury Basso Mouse Scale scores and footprint parameters, reduced Nissl body loss, and downregulated proinflammatory mediators in the spinal cord and lipopolysaccharide (LPS)-stimulated BV2 cells. LP17 enhanced LPS-induced mitophagy in BV2 cells and activated the AMPKα-PINK1-Parkin signaling pathway. Small interfering RNA-mediated AMPKα knockdown (si-AMPKα) blocked LP17-induced mitophagy and its anti-inflammatory effects. In conclusion, LP17 inhibits TREM1 to alleviate secondary SCI via the AMPKα-PINK1-Parkin-dependent microglial mitophagy pathway, making TREM1 a potential therapeutic target for SCI.
Middle-aged obesity and age-related anorexia leading to sarcopenia present a major public health burden. Similar age-associated patterns are observed across mammalian species, suggesting the involvement of conserved regulatory mechanisms. Age-dependent biphasic shifts in the balance between anabolic and catabolic signals of the adipose tissue-hypothalamus axis may contribute to both trends. Among hypothalamic mediators, neuropeptide Y (NPY) is a key anabolic (orexigenic and hypometabolic) peptide. This review summarizes current evidence on age-dependent changes in the effects of NPY on energy homeostasis. Activity of NPY shows a midlife increase in animal studies, promoting age-related obesity, whereas its decline in old age - demonstrated in both experimental and human studies - may be involved in aging anorexia and sarcopenia. The activity of catabolic neuropeptides that inhibit the NPY system changes in an opposite pattern across the lifespan. Age-related changes should be considered in drug development targeting NPY and its receptors.
Oxytocin plays an important and well-known role in promoting social interaction in maternal, sexual and interpersonal behaviors. In addition, it has been increasingly linked to the modulation of pain, fear and cognitive processes such as attention and memory, which seems to be supported by the presence of oxytocin receptors in various brain areas. With this in mind, this study aims to investigate the effects of inhaled oxytocin on fear, pain perception and aversive memory in humans, as well as the relationship between them. The study involved 65 healthy female volunteers who were randomly assigned to receive either intranasal oxytocin (40 IU) or a placebo. The participants were divided into two experimental designs, A and B, with within-subject comparisons conducted. Its effects on pain were investigated by means of the Cold Pressor Test, keeping records of pain threshold and tolerance, as well as of its intensity using the Visual Analog Scale (VAS) and its classification using the McGill Pain Questionnaire. The effects on fear were investigated using the Trauma Film Paradigm, with the intensity of fear measured by means of the VAS, as well as aversion, attention and immersion in the film. A questionnaire was deployed to assess aversive declarative memory at different intervals. Intrusive aversive memories were analyzed by means of quantitative and qualitative records taken over 7 days. Our results showed that oxytocin increased dislike of pain when the painful stimulus occurred in an aversive context, which may have contributed to a negative mood state. In addition, oxytocin attenuated intrusive memories in such a way as to reduce their frequency and the suffering they caused. Altogether, the results suggest that intranasal oxytocin can modulate the subjective perception of pain, fear and aversive memory in humans, depending on the context in which the stimuli occur and their biopsychosocial relevance.
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a highly conserved neuropeptide with well-established neuroprotective actions in the central and peripheral nervous system. Owing to the developmental and functional relationship between the brain and the retina, growing attention has focused on the retinal distribution of PACAP and its receptors, as well as their potential translational relevance. The aim of the present review is to summarize occurrence and distribution of PACAP and its receptors in different vertebrate species.Comparative studies across vertebrates (including fish, birds, rodents, and primates) demonstrate a remarkably conserved retinal expression pattern, particularly for the PAC1 receptor. PACAP signaling components are predominantly localized to the inner retinal layers, with frequent expression in amacrine and bipolar cells and, in some species, Müller glia. Early embryonic expression observed in several species suggests roles in retinal neurogenesis, differentiation, and synaptic maturation, while persistent adult expression supports involvement in synaptic modulation, circadian regulation, and neuronal maintenance.Extensive experimental evidence from rodent models shows that PACAP exerts robust retinoprotective effects in excitotoxic, ischemic, diabetic, and glaucomatous injury paradigms. These protective actions are associated with modulation of pro-survival signaling pathways, attenuation of inflammatory responses, and reduction of apoptotic processes. Importantly, human retinal tissue exhibits comparable localization patterns, and in vitro studies in human-derived retinal cells confirm cytoprotective effects.The evolutionary conservation of retinal PACAP signaling underscores its fundamental physiological importance and supports further investigation of PACAP-based translational strategies for vision-threatening retinal disorders.
Heat stress due to exposure to high environmental temperatures influences thermoregulation and metabolic balance in poultry, and central neuropeptidergic pathways play a critical role in these responses. Central administration of neuropeptide Y (NPY) induces hypothermia under thermoneutral conditions (CT) in chicks but its thermoregulatory role during high environmental temperatures remains unclear. In the present study, male chicks were intracerebroventricularly injected with 1 nmol NPY, followed by exposure to CT (30 ± 1 °C), moderate ambient temperature (MT: 35 ± 1 °C) or high ambient temperature (HT: 40 ± 1 °C) for 2 h. We confirmed the hypothermic effect of central NPY under CT. Interestingly, central NPY induced hyperthermia under HT, but not MT. Central injection of NPY reduced plasma glucose concentration during CT and HT. Additionally, diencephalic dopamine concentrations increased under both CT and HT following central injection of NPY, while norepinephrine to 3-methoxy-4-hydroxyphenylglycol turnover decreased. In conclusion, the shift from a hypothermic role under CT to hyperthermic action under HT of NPY, combined with dopaminergic and metabolic modulations, suggest catecholamine metabolism may be involved with the differential thermoregulatory role of NPY.
Galanin (GAL), a neuropeptide produced in both the central and peripheral nervous systems, is implicated in various physiological processes, including reproduction in vertebrates. Yet, the role of GAL is not understood in reptilian reproduction. This study aimed to investigate the impact of the galanin receptor agonist (GALR-A) on the reproductive axis during both the breeding and non-breeding phases of the ovarian cycle in the gecko Hemidactylus frenatus. During the recrudescence phase, administration of either a low (0.2 μg) or high dose (2 μg) of GALR-A did not affect either the follicular development up to stage IV (early vitellogenic) or gonadotropin-releasing hormone (GnRH) immunoreactivity in the median eminence (ME) and pars distalis of the pituitary gland (PD). However, stage V (late vitellogenic) follicles were absent in the ovary, in contrast to their appearance in experimental controls. In the regression phase, follicle-stimulating hormone (FSH) treatment led to the development of stage IV and V follicles, whereas treatment with a combination of 2 μg GALR-A and FSH did not stimulate the development of these follicles. In addition, in vitro treatment with GALR-A significantly reduced ovarian estradiol levels. Overall, these results suggest that GALR-A treatment disrupts the seasonal recrudescence potentially by interfering with the steroidogenesis and growth of vitellogenic follicles at advanced stages directly at the ovarian level in the gecko.
Vascular dementia (VaD), primarily caused by chronic cerebral hypoperfusion (CCH), is characterized by progressive cognitive decline associated with neurovascular dysfunction. The present study aimed to investigate whether systemic administration of irisin, an exercise-induced myokine, modulates cognitive performance and VEGF-associated angiogenic signaling in the hippocampus under CCH conditions. Thirty-eight adult male Wistar albino rats were randomly assigned to five groups: control, sham, irisin, ischemia, and ischemia + irisin. CCH was induced via permanent bilateral common carotid artery occlusion. Irisin (100 ng/kg) was administered intraperitoneally three times per week for four weeks. Cognitive performance was assessed using the Morris Water Maze, and VEGF-positive vascular profiles were quantified within a standardized hippocampal area (1 mm2 per section). CCH resulted in significant impairments in spatial learning and memory, accompanied by a reduction in VEGF-positive vascular profiles in the hippocampus. In healthy rats, irisin administration was associated with improved memory performance and increased VEGF-positive vascular profiles. In ischemic rats, irisin treatment was linked to partial improvements in memory parameters and VEGF-associated vascular changes, although these effects did not reach statistical significance. Learning-phase outcomes were more variable. Notably, the number of VEGF-positive vascular profiles positively correlated with spatial memory performance. These findings suggest that beyond its known neuroprotective properties, irisin may contribute to cognitive support through modulation of angiogenesis-associated signaling under CCH. While further studies are required to clarify optimal dosing strategies and mechanistic pathways, irisin may represent a promising adjunctive candidate for vascular cognitive impairment, particularly in individuals unable to engage in regular physical exercise.
The rapid aging of the global population is contributing to a sharp increase in dementia cases, with Alzheimer's disease (AD) accounting for the majority of diagnoses. The most widely accepted theory explaining AD pathogenesis is the amyloid cascade hypothesis, which implicates the accumulation of amyloid-β (Aβ) peptides, particularly the Aβ1-42 isoform, as a key pathogenic event. Oligomeric forms of Aβ1-42 act as bioactive neurotoxic peptides, disrupting synaptic function and neuronal homeostasis. Despite its frequent use in animal models, Aβ1-42 presents challenges due to its high cost and complex handling. In this study, we applied bioinformatic and structural approaches to identify a minimal peptide motif within Aβ1-42 capable of reproducing its neurobiological effects. We designed and evaluated the peptide fragment Aβ16-21 (KLVFFA), which corresponds to the hydropHobic core of Aβ1-42 and is a critical determinant of peptide aggregation and bioactivity. We assessed the cognitive and biochemical effects of intracerebroventricular administration of Aβ16-21 in mice and compared its impact to that of Aβ1-42. Behavioral testing revealed significant deficits in both working and reference memory in animals treated with either Aβ1-42 or Aβ16-21, with no clear dose-dependent effects. Biochemical evaluation demonstrated increased levels of the anti-inflammatory cytokine IL-10 in the cortex and hippocampus after Aβ16-21 administration, while TNF-α levels remained unchanged, indicating peptide-dependent modulation of neuroimmune responses. Notably, Aβ16-21 consistently formed neurotoxic oligomeric assemblies despite its reduced length. These findings demonstrate that Aβ16-21 retains key neurotoxic and immunomodulatory properties of full-length Aβ1-42, supporting its use as a biologically relevant minimal neuroactive peptide. Due to its structural simplicity, reproducibility, lower cost, and experimental accessibility, Aβ16-21 represents a valuable peptide-based tool for modeling AD-related neuropeptide dysfunction in preclinical research.
