👤 Mohammad Mahdi Mohammadi

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive memory impairment and cognitive decline, significantly impacting the quality of life for millions worldwide. Understanding the intricate molecular pathways linking AD pathology to memory dysfunction is crucial for developing effective therapies. This narrative review aims to elucidate the key molecular mechanisms underlying memory impairment in AD. We conducted a comprehensive literature search across major scientific databases (e.g., PubMed, Scopus, Web of Science) focusing on peer-reviewed studies (original research, reviews) exploring the molecular links between AD pathology and memory deficits. The review identifies and details several interconnected molecular pathways driving memory impairment in AD: (1) Synaptic dysfunction and neuronal loss triggered by amyloid-β (Aβ) peptide accumulation and aggregation; (2) Intracellular transport disruption and neurodegeneration caused by tau protein hyperphosphorylation and aggregation; (3) Exacerbation of cognitive deficits by neuroinflammation, mediated through activated microglia and pro-inflammatory cytokines (e.g., IL-1β, TNF-α, IL-6); (4) Impairment of synaptic plasticity and cognitive function due to dysregulation of neurotrophic factors, particularly brain-derived neurotrophic factor; (5) Contributory roles of oxidative stress, mitochondrial dysfunction, disrupted neurotransmission (e.g., acetylcholine, GABA), and apoptotic pathways. This review comprehensively unravels the critical molecular links between AD pathology and memory impairment, emphasizing the interplay of Aβ, tau, neuroinflammation, neurotrophic factor dysregulation, and other mechanisms. Targeting these interconnected pathways represents a promising strategic approach for developing therapies to mitigate cognitive decline and improve outcomes in AD patients. Show less

Peripheral nerve injury (PNI) is a significant health concern, affecting millions worldwide. Key neurotrophic factors, including nerve growth factor, brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor, have shown promise in facilitating neural regeneration. The effects of non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids have been extensively studied, emphasizing the importance of appropriate timing and duration of administration. Antioxidants such as vitamin E and melatonin have exhibited neuroprotective effects in animal models, but further research is necessary to determine their efficacy, optimal dosage, and administration in humans. Immunosuppressive agents like tacrolimus (FK506) and cyclosporin A have demonstrated substantial potential in enhancing peripheral nerve recovery. Supportive strategies, including physical therapy and neuromodulation techniques such as electrical and transcranial stimulation, have shown effectiveness in promoting nerve regeneration. Advances in bioengineering, including nerve conduits and stem cell transplantation, which mimic natural nerve repair mechanisms, hold considerable promise for improving PNI treatments. In conclusion, PNI therapy is progressing towards an integrative approach, combining surgical techniques with pharmacological interventions, bioengineering, and regenerative medicine to enhance outcomes while minimizing adverse effects. This review explores recent advancements in peripheral nerve regeneration using both natural and synthetic agents, highlighting the shift toward more comprehensive treatment strategies. Show less

Nicotine withdrawal during adolescence induces severe neurobehavioral disturbances and neurochemical alterations, including anxiety, depression, affective dysregulation, oxidative stress, and neuroinflammation. Current therapeutic options for managing nicotine dependence remain suboptimal. This study investigated the neuroprotective potential of naringenin (NG) in alleviating behavioral and biochemical sequelae of nicotine withdrawal in adolescent rats. Male adolescent Wistar rats were allocated into eight groups and subjected to nicotine exposure (1 mg/kg) and NG treatment (50 or 100 mg/kg) across nicotine exposure and withdrawal phases. Behavioral assays (OFT, EPM, FST) were employed to evaluate anxiety- and depression-like behaviors. Neurochemical assessments of dopamine, serotonin, their metabolites (DOPAC, 5-HIAA), MAO-A activity, oxidative stress markers (MDA, Nit), antioxidant enzymes (SOD, CAT, TT), and neuroinflammatory/neurodegenerative biomarkers (GFAP, IL-10, BDNF, NSE) were conducted in prefrontal cortex (PFC) homogenates. Nicotine withdrawal significantly induced anxiety- and depression-like behaviors, disrupted monoaminergic balance, elevated MAO-A activity, and triggered oxidative and neuroinflammatory responses in the PFC. NG administration, particularly at 100 mg/kg across both phases, significantly ameliorated behavioral impairments, restored neurotransmitter homeostasis, inhibited MAO-A, suppressed lipid peroxidation and nitrosative stress, enhanced antioxidant defenses, reduced GFAP and NSE expression, and restored IL-10 and BDNF levels. NG exerts anxiolytic, antidepressant, antioxidant, and anti-inflammatory effects, likely via modulation of monoaminergic pathways and suppression of neuroinflammation and oxidative stress. These findings underscore the potential of NG as a promising candidate for mitigating neuropathological effects associated with nicotine withdrawal-induced neuropathology, particularly during adolescence. Show less

Alzheimer's disease (AD), a primary cause of dementia, involves cognitive decline and neuroinflammation. Human hair follicle stem cells (hHFSCs) have shown neuroprotective potential, but their effects on immune modulation, especially in xenogeneic transplantation, remain unclear. This study aimed to investigate the therapeutic potential of hHFSCs against memory impairment and neuroinflammation induced by streptozotocin (STZ) in male rats. Adult male Sprague-Dawley rats were intracerebroventricularly injected with STZ (3 mg/kg) to induce AD-like cognitive deficits. hHFSC transplantation (1 × 10 STZ significantly impaired memory in passive avoidance test, but not Y-maze. hHFSC significantly improved memory performance. mRNA analysis revealed elevated BDNF, TGFβ, and GFAP levels in the STZ group. The increased TGFβ and GFAP levels continued following hHFSC treatment, indicating a compensatory response. Moreover, pro-inflammatory factors (IL-1β, IL-6, and TNFα) were upregulated following hHFSC therapy, suggesting persistent neuroinflammation. hHFSC led to anti-inflammatory effects through the elevation of IL-10. In addition, hHFSCs significantly reduced hippocampal atrophy and neuronal loss induced by STZ. hHFSCs exhibit partial neuroprotective effects against STZ-induced memory impairment. The simultaneous upregulation of pro- and anti-inflammatory markers underscores the complexity of the inflammatory response in this xenogeneic model. Future investigations should consider immunocompromised models or immunosuppressive protocols better to isolate the therapeutic effects of hHFSCs from immune responses. Show less

The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for Alzheimer's disease (AD) and is linked to poorer cerebrovascular health. Cerebrovascular reactivity (CVR), an indicator of vascular reserve, and cerebral pulsatility (CP), a marker of vascular stiffness, are sensitive biomarkers of early vascular dysfunction associated with aging and AD. However, the relationship between APOE4 status and these cerebrovascular metrics remains unclear. This study investigated whether the APOE genotype influences longitudinal changes in CVR and CP, and their association with cognitive performance in cognitively unimpaired individuals. We utilized the PREVENT-AD cohort, including 101 APOE4 carriers (30 males and 71 females) and 152 non-APOE4 carriers (48 males and 104 females) aged 55 and older. Relative CVR and CP were derived from resting state functional magnetic resonance imaging data, with regional values extracted from cerebral arterial territories. Results indicated significant interactions between APOE4 status and relative CVR in the left middle cerebral artery and left posterior cerebral artery (PCA) territories. APOE4 status disaggregated analyses revealed that APOE4 carriers uniquely presented a significant decline in relative CVR within the left PCA. Furthermore, sex-specific effects were identified, with female APOE4 carriers having lower relative CVR in the right anterior cerebral artery territory compared to female non-carriers. Importantly, higher relative CVR was positively associated with better cognitive performance in APOE4 carriers. No significant effects of APOE4 status on CP were found. Together, these findings suggest that relative CVR may be an important early measure of cerebrovascular health and cognition in cognitively intact APOE4 carriers. Show less

Gut brain axis can affect the incidence of Alzheimer's disease (AD). Probiotics restore the homeostasis of gut dysbiosis and prevent AD. Here, we evaluated the impact of Saccharomyces boulardii on rats with lipopolysaccharide (LPS)-induced amyloidogenesis. Rats were classified into four groups: (1) Control (saline), (2) LPS 250 µg/kg (saline + LPS), (3) S. boulardii (10 Show less

Patients experiencing premature cardiovascular events (males: <55 years; females: <65 years) represent a high-risk subgroup within the atherosclerotic cardiovascular disease (ASCVD) population. Elevated lipoprotein(a) (Lp[a]) is an independent, genetic, causal risk factor for ASCVD. Lp(a) distribution among patients with premature ASCVD is poorly characterized. This study aimed to describe Lp(a) distribution and baseline characteristics in a large real-world sample of patients with premature ASCVD. We identified 17,594 patients with premature ASCVD who had Lp(a) values from US Medicare, Medicaid, and commercial plans between January 2016-September 2022. Mean age (SD) was 50.9 (10.1) years, most patients were female (68.9%), and half (52.2%) were not prescribed lipid-lowering therapy. Lp(a) levels ≥125, ≥175, and ≥225 nmol/L occurred in 26.8%, 18.8%, and 11.5%, respectively. Black patients had higher median (Q1-Q3) Lp(a) levels (111.0 [51.1-206.0] nmol/L) than Asian (35.0 [14.4-100.0] nmol/L), Hispanic (31.0 [10.9-95.0] nmol/L), or White patients (31.0 [10.7-110] nmol/L). In one of the largest studies in the US investigating Lp(a) distribution in premature ASCVD, we found over a quarter of patients had elevated Lp(a) (≥125 nmol/L). Show less

The present study aimed to investigate whether supplementation of modified lysophospholipids (LPLs) in the diet of broiler breeders can benefit their offspring. A total of 264 49-week-old breeders (Ross 308) were allocated and fed based on a 2 × 2 factorial arrangement with two levels of dietary energy (normal energy = 2800 kcal/kg and low energy = 2760 kcal/kg) and two LPL levels (0 and 0.5 g/kg) for periods of 8 and 12 weeks. The offspring were assessed for growth performance, serum parameters, hepatic antioxidative capability, and expression of genes involved in liver β-oxidation at 7 days old. The LPL inclusion improved ( Show less

Since obesity and diabetes are prevalent worldwide, identifying the factors affecting these two conditions can effectively alter them. We decided to investigate the expression of obesity and diabetes genes in infants with birth weights lower than 2500 g in comparison with infants with normal birth weights. 215 healthy infants between the ages of 5-6 months were used in the current case-control research, which was conducted at health and treatment facilities in Kermanshah. Infants who were healthy were chosen for the research after their weight and height were measured and compared to the WHO diagram to ensure that they were well-grown and in good health. There were 137 infants in the control group and 78 infants in the case group. All newborns had 5 cc of blood drawn intravenously. To assess the expression of the genes MC4R, MTNR1B, PTEN, ACACB, PPAR-γ, PPAR-α, NRXN3, NTRK2, PCSK1, A2BP1, TMEM18, LXR, BDNF, TCF7L2, FTO and CPT1A, blood samples were gathered in EDTA-coated vials. Chi-square, Mann-Whitney U, and Spearman analyses were used to examine the data. A significant inverse correlation between birth weight and obesity and diabetes genes, including MTNR1B, NTRK2, PCSK1, and PTEN genes (r= -0.221, -0.235, -0.246, and - 0.418, respectively). In addition, the LBW infant's expression level was significantly up-regulated than the normal-weight infants (P = 0.001, 0.007, 0.001, and < 0.001, respectively). The expression level of the PPAR-a gene had a significantly positive correlation with birth weight (r = 0.19, P = 0.005). The expression level of the PPAR-a gene in the normal-weight infants was significantly up-regulated than the LBW infants (P = 0.049). The expression levels of MTNR1B, NTRK2, PCSK1, and PTEN genes were up-regulated in the LBW infants; however, the expression level of PPAR-a gene was significantly down-regulated in the LBW infants compared to the infants with normal birth weight. Show less

Type 2 diabetes (T2D) is a major health and economic burden worldwide. Despite the availability of multiple drugs for short-term management, sustained remission of T2D is currently not achievable pharmacologically. Intracerebroventricular administration of fibroblast growth factor 1 (icvFGF1) induces sustained remission in T2D rodents, propelling intense research efforts to understand its mechanism of action. Whether other FGFs possess similar therapeutic benefits is currently unknown. Here, we show that icvFGF4 also elicits a sustained antidiabetic effect in both male db/db mice and diet-induced obese mice by activating FGF receptor 1 (FGFR1) expressed in glucose-sensing neurons within the mediobasal hypothalamus. Specifically, FGF4 excites glucose-excited (GE) neurons while inhibiting glucose-inhibited (GI) neurons. Moreover, icvFGF4 restores the percentage of GI neurons in db/db mice. Importantly, intranasal delivery of FGF4 alleviates hyperglycemia in db/db mice, paving the way for non-invasive therapy. We conclude that icvFGF4 holds significant therapeutic potential for achieving sustained remission of T2D. Show less

Chronic age-related imbalance is a common cause of falls and subsequent death in the elderly and can arise from dysfunction of the vestibular system, an elegant neuroanatomical group of pathways that mediates human perception of acceleration, gravity, and angular head motion. Studies indicate that 27-46% of the risk of age-related chronic imbalance is genetic; nevertheless, the underlying genes remain unknown. The cohort consisted of 50,339 cases and 366,900 controls in the Million Veteran Program. The phenotype comprised cases with two ICD diagnoses of vertigo or dizziness at least 6 months apart, excluding acute or recurrent vertiginous syndromes and other non-vestibular disorders. Genome-wide association studies were performed as individual logistic regressions on European, African American, and Hispanic ancestries followed by trans-ancestry meta-analysis. Downstream analysis included case-case-GWAS, fine mapping, probabilistic colocalization of significant variants and genes with eQTLs, and functional analysis of significant hits. Two significant loci were identified in Europeans, another in the Hispanic population, and two additional in trans-ancestry meta-analysis, including three novel loci. Fine mapping revealed credible sets of intronic single nucleotide polymorphisms (SNPs) in MLLT10 - a histone methyl transferase cofactor, BPTF - a subunit of a nucleosome remodeling complex implicated in neurodevelopment, and LINC01224 - a proto-oncogene receptor tyrosine kinase. Despite the difficulties of phenotyping the nature of chronic imbalance, we replicated two loci from previous vertigo GWAS studies and identified three novel loci. Findings suggest candidates for further study and ultimate treatment of this common elderly disorder. Show less

The association of genetic and dietary factors with occurrence and progression of chronic diseases such as metabolic syndrome (MetS) has long been addressed but there is a lack of evidence for complex interrelationships, including direct and indirect effects of these variables. Hence, this study is aimed at evaluating the mediating role of glycemic indices in the association of melanocortin-4 receptor (MC4R) rs17782313 polymorphism, sociodemographic, and psychological factors with the risk of MetS in obese adults using structural equation modeling. We performed a cross-sectional analysis of data from 287 apparently healthy adults. Dietary glycemic index (GI) and glycemic load (GL) were calculated from a validated 147-item food frequency questionnaire (FFQ). MC4R s17782313 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Structural equation modeling was used to explore direct and indirect effects of genetic and nongenetic factors on MetS. MC4R gene variant was directly associated with the risk of MetS ( Our data may state a hypothesis of the mediating effect of quantity and quality of carbohydrates consumed in relationship between genetic susceptibility to obesity and cardiometabolic risk factors. Further analyses should be carried out in high-quality cohort studies in order to confirm the findings. Show less

Evidence shows the role of polymorphisms in rs17782313 MC4R gene with increased risk of obesity in Asians adult. In the current report, we investigated the interaction between rs17782313 MC4R gene and major dietary patterns on α-melanocyte stimulating hormone (α-MSH), Agouti-related peptide (AgRP), serum lipids and blood pressure among obese individuals. This cross-sectional study was performed in 288 obese adults between 20 and 50 years of age. Anthropometric measurements and biochemical assays were conducted with standard methods. To evaluate appetite, the Visual Analogue Scale (VAS) was used. Dietary patterns were obtained by principal component analysis (PCA). Genotyping of rs17782313 was assessed by restriction fragment length polymorphism (PCR-RFLP) method. Three major dietary patterns were extracted: Prudent Dietary Pattern (PDP), Legume Dietary Pattern (LDP) and Mixed Dietary Pattern (MDP). Higher PDP score was associated with reduced SBP and insulin concentration while highest MDP score was associated with lower TG concentration (P < 0.05). Significant interactions were observed between higher adherence to PDP and rs17782313 CC genotype on increased SBP (P The findings of the current study showed that being on CC genotype of rs17782313 polymorphism made obese individuals more prone to have higher SBP, insulin and AgRP even in highest adherence to PDP. However, adherence to MDP could attenuate the risky effects of being on CC genotype of rs17782313 by reducing serum TG concentrations. Level V, cross-sectional descriptive study. Show less

Notch suppression by gamma-secretase inhibitors is a valid approach against melanoma. However, most of studies have evaluated the short-term effect of DAPT on tumor cells or even cancer stem cells. In the present study, we surveyed the short-term and long-term effects of DAPT on the stem cell properties of A375 and NA8 as melanoma cell lines. The effects of DAPT were tested both Show less

Thirty-six 12-week-old breeder roosters (Ross 308) were randomly allocated into three groups to receive L-carnitine (LC): LC-0, LC-250 or LC-500 mg/kg of diet to evaluate the effects of dietary LC on the expression of apoptotic-related genes and desaturases and elongase mRNA transcript levels, in the cockerel testicles. Alteration of Bak (Bcl2 antagonist/killer), Bcl2, Cas3, Cas8, Cas9, Elovl2, Elovl4, Elovl5, Fads1, Fads2 and Scd expression at 24 and 34 weeks of age was compared by real-time quantitative PCR. The expression of Bcl2 and Elovl5 was significantly up-regulated (p < .05), while Cas8 expression (p < .05) and Bak/Bcl2 ratio were reduced (p < .02) in the cockerel testicles at 24 weeks of age. Although Bak mRNA abundance decreased by dietary LC, Bak/Bcl2 ratio was not affected by the treatments at 34 weeks of age. The expression of Cas3 was down-regulated, while Fads2 was up-regulated in the cockerel testicles by dietary LC at 34 weeks of age (p < .05). The results demonstrate the beneficial effects of LC supplementation in suppression of the Bak/Bcl2 ratio by altering Bak and Bcl2 mRNA abundance and, ultimately, prevention of apoptosis. Furthermore, LC increased the expression of Elovl5 and Fads2 genes which are involved in the metabolism of long chain fatty acids. Show less

Obesity is a significant risk factor for a number of chronic diseases, including diabetes, cardiovascular diseases, and cancer. Obesity usually results from a combination of causes and contributing factors, including genetics and lifestyle choices. Many studies have shown an association of single nucleotide polymorphisms (SNPs) in the fat mass and obesity-associated ( We enrolled 130 obese patients and 83 healthy weight controls and calculated their BMI. Genomic DNA was extracted from peripheral blood and the frequency of rs9939609 and rs17782313 polymorphisms in Significant associations were found between This study shows a relationship between Show less

Congenital hypogonadotropic hypogonadism (CHH) and its anosmia-associated form (Kallmann syndrome [KS]) are genetically heterogeneous. Among the >15 genes implicated in these conditions, mutations in FGF8 and FGFR1 account for ~12% of cases; notably, KAL1 and HS6ST1 are also involved in FGFR1 signaling and can be mutated in CHH. We therefore hypothesized that mutations in genes encoding a broader range of modulators of the FGFR1 pathway might contribute to the genetics of CHH as causal or modifier mutations. Thus, we aimed to (1) investigate whether CHH individuals harbor mutations in members of the so-called "FGF8 synexpression" group and (2) validate the ability of a bioinformatics algorithm on the basis of protein-protein interactome data (interactome-based affiliation scoring [IBAS]) to identify high-quality candidate genes. On the basis of sequence homology, expression, and structural and functional data, seven genes were selected and sequenced in 386 unrelated CHH individuals and 155 controls. Except for FGF18 and SPRY2, all other genes were found to be mutated in CHH individuals: FGF17 (n = 3 individuals), IL17RD (n = 8), DUSP6 (n = 5), SPRY4 (n = 14), and FLRT3 (n = 3). Independently, IBAS predicted FGF17 and IL17RD as the two top candidates in the entire proteome on the basis of a statistical test of their protein-protein interaction patterns to proteins known to be altered in CHH. Most of the FGF17 and IL17RD mutations altered protein function in vitro. IL17RD mutations were found only in KS individuals and were strongly linked to hearing loss (6/8 individuals). Mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH. Show less

Study of molecular responses to central nervous system injury would be helpful for controlling the harmful pathways post-injury and triggering the useful pathways required for the treatment of injury. To investigate the expression level of liver X receptor α (LXRα) which has anti-inflammatory effects and pro-apoptotic Bcl-2-associated X protein (Bax) upon spinal cord injury (SCI). To induce SCI, transection was carried out at T9 level of male Wister rats. Approximately 8 mm of rostral, caudal, and epicenter tissues of injured sites in treated rats were chosen for quantitative real-time polymerase chain reaction at the 6, 24, and 72 hours, and 7 and 10 days post-surgery. Our results showed a complicated temporal and spatial pattern of alteration in LXRα and Bax mRNA expression levels after SCI. LXRα expression level followed a homologues pattern (additive and subtractive wave) with a difference in time at three areas of studied. Rostral, caudal, and epicenter expression patterns of Bax were dissimilar in these areas. Gradual increase in the expression of Bax without any decrease at the rostral area was observed, presumably indicating the active transcription process of this gene, regardless of its protein situation. A time lapse significant change in Bax expression level was observed only in the epicenter of injury, emphasizing that apoptotic responses are limited to this area. Furthermore, an increase in LXRα transcription level was observed first in rostral area and then extended to epicentral and caudal areas, implying that inflammation responses extended from rostral to caudal areas. Show less

Identification of casual mutations in Hereditary Multiple Exostoses (HME) is important because of similar conditions in which multiple exostoses occur. Therefore mutation analysis can help to confirm the clinical diagnosis and to improve the management of therapy. HME is an inherited disorder of bone growth. HME can be referred to by various names such as Heredity Multiple Exostoses, Hereditary Multiple Osteochondromata, Multiple Carthaginous Exostoses, etc. People who have HME grow exostoses, or bony bumps, on their bones which can vary in size, location and number depending on the individual. HME is inherited in an autosomal dominant manner with an estimated prevalence of 1/50,000 in western countries. At least three loci (EXT1, EXT2 and EXT3) thought to be involved in this skeletal disease. Approximately 90% of affected families possess mutations in the coding regions of EXT1 and EXT2 genes and the majority of these mutations cause loss of function. EXT1 and EXT2 genes encode related members of a putative tumor suppressor family. In this first report from Iran we identified a frame shift mutation (1100-1101 insA) in exon 3 of EXT1 gene in a family being suspicious of HME. This mutation leads to a premature stop codon and previously not described. Additionally, we have found an unreported silent mutation in the exon six of EXT1 gene with uncertain significance. Show less