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Background The underlying disease mechanism of neuropsychiatric symptoms (NPS) in dementia remains unclear. Cerebrospinal fluid (CSF) biomarkers for synaptic and axonal degeneration may provide novel neuropathological information for their occurrence. The aim was to investigate the relationship between NPS and CSF biomarkers for synaptic (neurogranin [Ng], growth-associated protein 43 [GAP-43]) and axonal (neurofilament light [NFL]) injury in patients with dementia. Methods A total of 151 patients (mean age ± SD, 73.5 ± 11.0, females n  = 92 [61%]) were included, of which 64 had Alzheimer’s disease (AD) (34 with high NPS, i.e., Neuropsychiatric Inventory (NPI) score > 10 and 30 with low levels of NPS) and 18 were diagnosed with vascular dementia (VaD), 27 with mixed dementia (MIX), 12 with mild cognitive impairment (MCI), and 30 with subjective cognitive impairment (SCI). NPS were primarily assessed using the NPI. CSF samples were analyzed using enzyme-linked immunosorbent assays (ELISAs) for T-tau, P-tau, Aβ1–42, Ng, NFL, and GAP-43. Results No significant differences were seen in the CSF levels of Ng, GAP-43, and NFL between AD patients with high vs low levels of NPS (but almost significantly decreased for Ng in AD patients < 70 years with high NPS, p  = 0.06). No significant associations between NPS and CSF biomarkers were seen in AD patients. In VaD ( n  = 17), negative correlations were found between GAP-43, Ng, NFL, and NPS. Conclusion Our results could suggest that low levels of Ng may be associated with higher severity of NPS early in the AD continuum (age < 70). Furthermore, our data may indicate a potential relationship between the presence of NPS and synaptic as well as axonal degeneration in the setting of VaD pathology.

Loss of calcium homeostasis, a shared feature of Alzheimer’s Disease (AD) and Traumatic Brain Injury (TBI), activates enzyme-dependent cascades that promote protein misfolding, degrade synaptic architecture, impair axonal transport, and lead to neuronal death. Epidemiological studies identify TBI as a major risk factor for AD, yet the mechanistic basis for this association remains incompletely understood. Evidence from human and experimental studies implicate calcium dysregulation as a central link, triggering interconnected kinase, phosphatase, and protease networks that drive AD hallmark pathology, including amyloid-β (Aβ) accumulation and tau hyperphosphorylation. The calcium-dependent protease calpain is a key node in this network, regulating downstream enzyme activity, and cleaving essential scaffolding and signaling proteins. Selective vulnerability of the hippocampus and white matter to calcium-mediated damage may underlie cognitive deficits common to both conditions. In preclinical TBI and AD models, pharmacological inhibition of calcium-dependent enzymes confers neuroprotection. Recognizing disrupted calcium signaling as an upstream driver of post-traumatic neurodegeneration may enable early interventions to reduce AD risk among TBI survivors.

The formation of the central nervous system is a meticulously planned and intricate process. Any modification to this process has the potential to disrupt the structure and operation of the brain, which could result in deficiencies in neurological growth. When neurotoxic substances are present during the early stages of development, they can be exceptionally dangerous. Prenatally, the immature brain is extremely vulnerable and is therefore at high risk in pregnant women associated with occupational exposures. Lead, fluoride, aluminum, and cadmium are examples of possibly toxic trace elements that have been identified as an environmental concern in the aetiology of a number of neurological and neurodegenerative illnesses. SIRT1, a member of the sirtuin family has received most attention for its potential neuroprotective properties. SIRT1 is an intriguing therapeutic target since it demonstrates important functions to increase neurogenesis and cellular lifespan by modulating multiple pathways. It promotes axonal extension, neurite growth, and dendritic branching during the development of neurons. Additionally, it contributes to neurogenesis, synaptic plasticity, memory development, and neuroprotection. This review summarizes the possible role of SIRT1 signalling pathway in potentially toxic trace elements -induced neurodevelopmental toxicity, highlighting some molecular pathways such as mitochondrial biogenesis, CREB/BDNF and PGC-1α/NRF1/TFAM.

The majority of patients affected with lysosomal storage disorders (LSD) exhibit neurological symptoms. For mucopolysaccharidosis type IIIC (MPSIIIC), the major burdens are progressive and severe neuropsychiatric problems and dementia, primarily thought to stem from neurodegeneration. Using the MPSIIIC mouse model, we studied whether clinical manifestations preceding massive neurodegeneration arise from synaptic dysfunction. Reduced levels or abnormal distribution of multiple synaptic proteins were revealed in cultured hippocampal and CA1 pyramidal MPSIIIC neurons. These defects were rescued by virus-mediated gene correction. Dendritic spines were reduced in pyramidal neurons of mouse models of MPSIIIC and other (Tay-Sachs, sialidosis) LSD as early as at P10. MPSIIIC neurons also presented alterations in frequency and amplitude of miniature excitatory and inhibitory postsynaptic currents, sparse synaptic vesicles, reduced postsynaptic densities, disorganized microtubule networks, and partially impaired axonal transport of synaptic proteins. Furthermore, postsynaptic densities were reduced in postmortem cortices of human MPS patients, suggesting that the pathology is a common hallmark for neurological LSD. Together, our results demonstrate that lysosomal storage defects cause early alterations in synaptic structure and abnormalities in neurotransmission originating from impaired synaptic vesicular transport, and they suggest that synaptic defects could be targeted to treat behavioral and cognitive defects in neurological LSD patients.

Alzheimer’s disease (AD), a predominant neurodegenerative disorder, is clinically characterized by progressive cognitive deterioration and behavioral deficits. An in-depth understanding of the pathogenesis and neuropathology of AD is essential for the development of effective treatments and early diagnosis techniques. The neuropathological signature of AD involves two hallmark lesions: intraneuronal neurofibrillary tangles composed of hyperphosphorylated tau aggregates and extracellular senile plaques containing amyloid-β (Aβ) peptide depositions. Although Aβ-centric research has dominated AD investigations over the past three decades, pharmacological interventions targeting Aβ pathology have failed to demonstrate clinical efficacy. Tau, a microtubule-associated protein predominantly localized to neuronal axons, orchestrates microtubule stabilization and axonal transport through dynamic tubulin interactions under physiological conditions. In AD pathogenesis, however, tau undergoes pathogenic post-translational modifications (PTMs), encompassing hyperphosphorylation, lysine acetylation, methylation, ubiquitination, and glycosylation. These PTM-driven alterations induce microtubule network disintegration, mitochondrial dysfunction, synaptic impairment, and neuroinflammatory cascades, ultimately culminating in irreversible neurodegeneration and progressive cognitive decline. This review synthesizes contemporary advances in tau PTM research and delineates their mechanistic contributions to AD pathogenesis, thereby establishing a framework for biomarker discovery, targeted therapeutic development, and precision medicine approaches in tauopathies. This review synthesizes contemporary advances in tau PTM research and delineates their mechanistic contributions to AD pathogenesis, thereby establishing a solid theoretical and experimental basis for the early diagnosis of neurodegenerative diseases, the discovery of therapeutic targets, and the development of novel therapeutic strategies.

Mitochondria play several vital roles in the brain cells, especially in neurons to provide synaptic energy (ATP), Ca2+ homeostasis, Reactive Oxygen Species (ROS) production, apoptosis, mitophagy, axonal transport and neurotransmission. Mitochondrial dysfunction is a well-established phenomenon in the pathophysiology of many neurological diseases, including Alzheimer’s disease (AD). Amyloid-beta (Aβ) and Phosphorylated tau (p-tau) proteins cause the severe mitochondrial defects in AD. A newly discovered cellular niche of microRNAs (miRNAs), so-called mitochondrial-miRNAs (mito-miRs), has recently been explored in mitochondrial functions, cellular processes and in a few human diseases. The mitochondria localized miRNAs regulate local mitochondrial genes expression and are significantly involved in the modulation of mitochondrial proteins, and thereby in controlling mitochondrial function. Thus, mitochondrial miRNAs are crucial to maintaining mitochondrial integrity and for normal mitochondrial homeostasis. Mitochondrial dysfunction is well established in AD pathogenesis, but unfortunately mitochondria miRNAs and their precise roles have not yet been investigated in AD. Therefore, an urgent need exists to examine and decipher the critical roles of mitochondrial miRNAs in AD and in the aging process. The current perspective sheds light on the latest insights and future research directions on investigating the contribution of mitochondrial miRNAs in AD and aging.

Structural plasticity is critical for the functional diversity of neurons in the brain. Experimental autoimmune encephalomyelitis (EAE) is the most commonly used model for multiple sclerosis (MS), successfully mimicking its key pathological features (inflammation, demyelination, axonal loss, and gliosis) and clinical symptoms (motor and non-motor dysfunctions). Recent studies have demonstrated the importance of synaptic plasticity in EAE pathogenesis. In the present study, we investigated the features of behavioral alteration and hippocampal structural plasticity in EAE-affected mice in the early phase (11 days post-immunization, DPI) and chronic phase (28 DPI). EAE-affected mice exhibited hippocampus-related behavioral dysfunction in the open field test during both early and chronic phases. Dendritic complexity was largely affected in the cornu ammonis 1 (CA1) and CA3 apical and dentate gyrus (DG) subregions of the hippocampus during the chronic phase, while this effect was only noted in the CA1 apical subregion in the early phase. Moreover, dendritic spine density was reduced in the hippocampal CA1 and CA3 apical/basal and DG subregions in the early phase of EAE, but only reduced in the DG subregion during the chronic phase. Furthermore, mRNA levels of proinflammatory cytokines (II1β, Tnfa, and Ifny) and glial cell markers (Gfap and Cd68) were significantly increased, whereas the expression of activity-regulated cytoskeleton-associated protein (ARC) was reduced during the chronic phase. Similarly, exposure to the aforementioned cytokines in primary cultures of hippocampal neurons reduced dendritic complexity and ARC expression. Primary cultures of hippocampal neurons also showed significantly reduced extracellular signal-regulated kinase (ERK) phosphorylation upon treatment with proinflammatory cytokines. Collectively, these results suggest that autoimmune neuroinflammation alters structural plasticity in the hippocampus, possibly through the ERK-ARC pathway, indicating that this alteration may be associated with hippocampal dysfunctions in EAE.

There is a general agreement in the scientific community that the degeneration of the nigrostriatal neurons in PD involves mitochondrial dysfunction, aggregation of alpha-synuclein to neurotoxic oligomers, dysfunction of protein degradation, oxidative stress, neuroinflammation and endoplasmic reticulum stress (Segura-Aguilar et al.,2014,2016a) and (ii) preclinical models that do not reflect what is happening in the disease since these models are based on exogenous neurotoxins that do not exist in dopaminergic neurons. Recently, it has been reported that the unilateral injection of aminochrome into the striatum induced a dysfunction of dopaminergic neurons characterized by (i) an imbalance between the level of dopamine and GABA as a consequence of lower release of dopamine; (ii) induction of a progressive contralateral behavior without significant loss of the nigrostriatal system; (iii) induction of mitochondrial dysfunction resulting in lower levels of ATP required for both axonal transport of synaptic vesicles and dopamine release; (iv) a significant decrease in the number of synaptic vesicles in the terminals; and (v) the induction of morphological changes in dopaminergic neurons (cell shrinkage) (Herrera et al.,2016). Aminochrome has been proposed as the endogenous neurotoxin that triggers the loss of dopaminergic neurons containing neuromelanin, since aminochrome induces mitochondrial dysfunction (Arriagada et al.,2004; Paris et al.,2011; Aguirre et al.,2012; Muñoz et al.,2012), protein degradation dysfunction (Zafar et al.,2006; Huenchuguala et al.,2014), endoplasmic reticulum stress (Xiong et al.,2014), oxidative stress (Arriagada et al.,2004) and the formation of neurotoxic oligomers of alpha-synuclein (Muñoz et al.,2015). [...]a new computer platform to explore new targets for new drugs is very important, but we also need to understand why we cannot translate successful results from preclinical to clinical studies to develop new pharmacological therapies.