Khadijeh Esmaeilpour

Mitochondrial calcium has emerged as a critical player in Alzheimer’s disease (AD), closely linked to neuronal dysfunction and cognitive decline seen in patients. Intracellular calcium signaling is essential for processes like synaptic plasticity, neuronal survival, and differentiation. When this balance is disturbed, it can trigger early pathological changes in AD, including the accumulation of amyloid-β (Aβ) peptides and the development of neurofibrillary tangles (NFTs), the hallmark features of the disease. Calcium imbalance in mitochondria disrupts their function, leading to reduced adenosine triphosphate (ATP) production, increased reactive oxygen species (ROS), and ultimately neuronal death. Aβ and tau act synergistically to further disturb calcium regulation, intensifying neurodegeneration. Excess mitochondrial calcium is also linked to altered activity of key calcium transporters, such as the mitochondrial calcium uniporter (MCU) and sodium/calcium/lithium exchanger (NCLX). Moreover, several genetic risk factors for AD, including ApoE4, PS1, PS2, and CALHM1, are known to influence intracellular calcium homeostasis. Building on this, the present study investigates how calcium dysregulation impairs mitochondrial function in AD. Understanding the mechanisms of calcium-induced mitochondrial dysfunction and identifying potential targets to control mitochondrial calcium levels could provide valuable insights for developing therapies against AD and other neurodegenerative diseases.

Alzheimer’s disease (AD) is the most common form of dementia, characterized by progressive cognitive decline driven by a complex interplay of genetic, environmental, and lifestyle factors. Increasing evidence highlights impaired synaptic plasticity as a major contributor to early cognitive deficits, often preceding neuronal loss. In particular, disruption of long-term potentiation (LTP) within the hippocampus, a region essential for learning and memory, plays a central role. Accumulation of amyloid β (Aβ) plaques and hyperphosphorylated tau proteins compromises synaptic integrity, leading to reduced synaptic density and altered protein expression critical for excitatory signaling. Additional mechanisms, including microglial activation and mitochondrial dysfunction, further aggravate synaptic impairment through inflammation and oxidative stress. Understanding these interconnected molecular and cellular disruptions offers crucial insight into the pathways underlying synaptic dysfunction in AD. By elucidating these mechanisms, future research can inform novel therapeutic strategies aimed at preserving synaptic function and slowing disease progression.

Microglia, the brain’s resident immune cells, are increasingly recognized as central players in the complex landscape of Alzheimer’s disease (AD). Traditionally associated with neuroinflammation, their roles extend far beyond, touching nearly every aspect of disease progression—from amyloid β (Aβ) and tau pathology to synaptic integrity and cognitive function. While early studies focused on their inflammatory responses, recent findings highlight a more nuanced picture: microglia can both protect and harm, depending on their state and the disease context. In this review, we examine the diverse functions of microglia at the crossroads of Aβ and tau pathology, emphasizing how dysfunction in their regulatory and clearance mechanisms can exacerbate neurodegeneration. We also explore how these insights are shaping therapeutic strategies aimed at modulating microglial activity to preserve brain health. By broadening the focus beyond inflammation alone, this work presents a more integrated view of microglial involvement in AD pathogenesis.

Melatonin supplementation shows potential therapeutic effects in Alzheimer’s disease (AD) by targeting impaired neurogenesis. Neurogenesis, the formation of new neurons after development, involves proliferation, migration, differentiation, and survival of neurons. Impaired neurogenesis is associated with AD, specifically in the subventricular zone (SVZ) and subgranular zone (SGZ), leading to hippocampal degeneration and memory impairment. Melatonin positively effects AD by regulating amyloid beta (Aβ)-induced neuroinflammation, reducing tau hyperphosphorylation, and enhancing adult neurogenesis through various signaling pathways. In addition, it has anti-apoptotic, antioxidative, and anti-inflammatory properties, suggesting its potential as a treatment option for AD progression. Furthermore, melatonin and sleep are closely linked, and an increase in sleep duration positively affects Aβ deposition. This review aims to examine the impact of AD pathologies on neurogenesis and explore the mechanisms by which melatonin may alleviate these pathologies, potentially promoting neurogenesis.

Microglial activation has emerged as a hallmark of neuroinflammation in Alzheimer’s disease (AD). Central to this process is the formation and accumulation of amyloid beta (Aβ) peptide and neurofibrillary tangles, both of which contribute to synaptic dysfunction and neuronal cell death. Aβ oligomers trigger microglial activation, leading to the release of pro-inflammatory cytokines, which further exacerbates neuroinflammation and neuronal damage. Importantly, the presence of activated microglia surrounding amyloid plaques is correlated with heightened production of cytokines such as interleukin (IL)-1β and tumor necrosis factor-alpha (TNF-α), creating a vicious cycle of inflammation. While microglia play a protective role by clearing Aβ plaques during the early stages of AD, their chronic activation can lead to detrimental outcomes, including enhanced tau pathology and neuronal apoptosis. Recent studies have highlighted the dualistic nature of microglial activation, showcasing both inflammatory (M1) and anti-inflammatory (M2) phenotypes that fluctuate based on the surrounding microenvironment. Disruption in microglial function and regulation can lead to neurovascular dysfunction, further contributing to the cognitive decline seen in AD. Moreover, emerging biomarkers and imaging techniques are unveiling the complexity of microglial responses in AD, providing avenues for targeted therapeutics aimed at modulating these cells. Understanding the intricate interplay between microglia, Aβ, and tau pathology is vital for developing potential interventions to mitigate neuroinflammation and its impact on cognitive decline in AD. This review synthesizes current findings regarding microglial activation and its implications for AD pathogenesis, offering insights into future therapeutic strategies. Graphical Abstract In AD, M1 microglia activation (via LPS, IFN-γ, TLR4/NF-κB/NLRP3/JAK-STAT/MAPK pathways) drives pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), oxidative stress, and neuroinflammation. Conversely, IL-4/IL-13 induce M2 polarization (via PPAR-γ/TREM-2), promoting anti-inflammatory factors (TGF-β, IL-10), Aβ phagocytosis, and neuroprotection. Dual microglial responses shape AD progression.

Background: Hertia plants have been used in traditional societies to treat pain, but no comprehensive research has been done to prove this plant's analgesic effects scientifically. Objectives: This study aimed to investigate the potential mechanism of action and analgesic and anti-inflammatory properties of Hertia intermedia leaf extract. Methodology: In this investigation, rats were given several doses of Hertia intermedia extract and its analgesic effects were assessed using the tail-flick, hot plate, and formalin tests. Rats were pre-treated with naloxone to have a look at the potential mechanism. The levels of inflammatory factors TNF-α and IL-6 in the blood of rats were assessed. To gain insight into the active substances, phytochemical tests were carried out. Results: The study's findings demonstrated the potential of Hertia intermedia leaf extract to alleviate pain and inflammation at various doses. The obtained extract was dark brown and gummy. The yield of extraction was 28% w/w. The result of the phytochemical study indicated the presence of flavonoids, tannins, steroids, and terpenoids. Analgesic and anti-inflammatory results showed that 150 mg/kg showed a strong analgesic effect on the hot plate; however, all tested doses (10-200 mg) showed analgesia in the tail flick test. Formalin-induced algesia was reduced by 150 mg. It is possible that the extract functions through opioid receptors because naloxone administrations also dramatically decreased the latency in response to pain in the hot plate and tail flick tests. Additionally, the anti-inflammatory properties of this extract were discovered by notably lowering the levels of IL-6 and TNF-α significantly at 150 mg/kg dose. Conclusion: According to the study, Hertia intermedia leaf extract mitigates inflammatory cytokines and has analgesic effects on the central and peripheral nervous systems.

Introduction: Rodents are highly dependent on maternal care after birth. Disturbing mother and pup interactions leads to detrimental alternations for the rat and the mother. Maternal separation (MS) is an accepted model for investigating disruption of mother and pup relationship. In addition to other detrimental effects, MS is a model known to induce permanent changes in learning and memory. Methylphenidate has been effective in memory enhancement in individuals suffering from memory deficits, attention‐deficit hyperactive disorder (ADHD), as well as healthy subjects for better performance in exams.Material and Methods: In this research, a 21‐day separation for 3 h was implemented, and the effects of MS on spatial and passive avoidance learning, and memory were evaluated in the mid‐adolescence period of rats, in both males and females. Also, a drug intervention of a high therapeutic dose of 5 mg per kg was used in a five‐day period in different control and MS groups. Morris water maze was utilized for spatial learning and memory analysis, and a shuttle box paradigm was used for passive avoidance learning and memory.Results: Through our behavioral tests, we have shown that MS can alter spatial learning and memory in males. On the other hand, females are protected from the detrimental effects of MS on spatial learning and memory. Furthermore, passive avoidance learning was not different among groups, be it male or female. However, in the case of memory evaluation in the passive avoidance test, the male did not exhibit a significant difference in step‐through latency. However, maternally separated females had poor performance in the memory phase with shorter step‐through latencies.Conclusion: Methylphenidate compensated for the deleterious effects of MS on learning and spatial memory for the male group and passive avoidance memory in the female group at the behavioral level.

The likelihood of substance dependency in offspring is increased in cases when there is a family history of drug or alcohol use. Mothering is limited by maternal addiction because of the separation. Maternal separation (MS) leads to the development of behavioural and neuropsychiatric issues in the future. Despite the importance of this issue, empirical investigations of the influences of maternal substance use and separation on substance use problems in offspring are limited, and studies that consider both effects are rare. This study aims to review a few studies on the mechanisms, treatments, genetics, epigenetics, molecular and psychological alterations, and neuroanatomical regions involved in the dependence of offspring who underwent maternal addiction and separation. The PubMed database was used. A total of 95 articles were found, including the most related ones in the review. The brain’s lateral paragigantocellularis (LPGi), nucleus accumbens (NAc), caudate-putamen (CPu), prefrontal cortex (PFC), and hippocampus, can be affected by MS. Dopamine receptor subtype genes, alcohol biomarker minor allele, and preproenkephalin mRNA may be affected by alcohol or substance use disorders. After early-life adversity, histone acetylation in the hippocampus may be linked to brain-derived neurotrophic factor (BDNF) gene epigenetics and glucocorticoid receptors (GRs). The adverse early-life experiences differ in offspring›s genders and rewire the brain›s dopamine and endocannabinoid circuits, making offspring more susceptible to dependence. Related psychological factors rooted in earlylife stress (ELS) and parental substance use disorder (SUD). Treatments include antidepressants, histone deacetylase inhibitors, lamotrigine, ketamine, choline, modafinil, methadone, dopamine, cannabinoid 1 receptor agonists/antagonists, vitamins, oxytocin, tetrahydrocannabinol, SR141716A, and dronabinol. Finally, the study emphasizes the need for multifaceted strategies to prevent these outcomes.