Alzheimer's disease (AD) is the world's most prevalent neurodegenerative disorder, characterized neuropathologically by senile plaques and neurofibrillary tangles formed by amyloid-β (Aβ) and tau, respectively. Notably, a subset of AD patients also exhibits pathological aggregates composed of TAR DNA-Binding Protein 43 (TDP-43). Clinically, the presence of TDP-43 copathology in AD correlates with more severe cognitive decline and faster disease progression. While previous studies have shown that TDP-43 can exacerbate Aβ toxicity and modulate its assembly dynamics by delaying fibrillization and promoting oligomer formation, the impact of the Aβ interaction on the structural dynamics and aggregation of TDP-43 remains unclear. Here, we employed all-atom discrete molecular dynamics simulations to study the direct interaction between Aβ42, the more amyloidogenic isoform of Aβ, and the amyloidogenic core region (ACR) of TDP-43, which spans residues 311-360 and is critical for TDP-43 aggregation. We found that monomeric Aβ42 could strongly bind to the ACR, establishing sustained contact through intermolecular hydrogen bonding. In contrast, simulation of ACR dimerization revealed a transient helix-helix interaction, experimentally known to drive the phase separation behavior of TDP-43. The binding of the ACR to an Aβ42 fibril seed resulted in significant structural transformation, with the complete unfolding of the helical region being observed. Furthermore, interaction with the Aβ42 fibril seed catalyzed the formation of a parallel, in-register intermolecular β-sheet between two ACR monomers. Collectively, our computational study provides important theoretical insights into TDP-43 pathology in AD, demonstrating that Aβ42, especially in its fibrillar form, may catalyze the pathogenic structural transformation within the TDP-43 ACR that initiates its aberrant aggregation.

Traditional analgesic opioid compounds, which act through μ opioid receptors (MORs), engender a high risk for misuse and dependence. κ opioid receptor (KOR) activation, a potential target for pain treatment, produces antinociception without euphoric side effects but results in dysphoria and aversion. Triazole 1.1 is a KOR agonist biased toward G-protein coupled signaling, potentially promoting antinociception without dysphoria. We tested whether triazole 1.1 could provide antinociception and its effects in combination with morphine. We employed a lactic acid abdominal pain model, which induced acute pain behaviors, decreased basal dopamine levels in the nucleus accumbens (NAc), and increased KOR function. We administered several interventions including triazole 1.1 (30 mg/kg) and morphine (12 or 24 mg/kg), individually and in combination. Triazole 1.1 alone reduced the pain behavioral response and changes to KOR function but did not prevent the reduction in basal dopamine levels. Morphine not only dose-dependently prevented behavioral pain responses but also elevated NAc dopamine and did not prevent the pain-induced increase in KOR function. However, combining low-dose morphine with triazole 1.1 prevents behavioral pain responses, changes to NAc dopamine levels, and changes to KOR function. Therefore, we present triazole 1.1 as a dose-sparing pain treatment to be used in combination with a lower dose of morphine, thus reducing the potential for opioid misuse.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is the leading cause of dementia, affecting nearly 55 million people across the world. One of the central pathological factors associated with AD is the aggregation of Aβ42, a peptide product cleaved through pathological processes in AD. Under pathological conditions, Aβ42 aggregates into insoluble plaques in the brain and impairs the function of neurons, which contributes to the cognitive decline associated with AD. Therefore, the modulation of Aβ42 aggregation is considered a potential therapeutic intervention for AD. Using an Oligoquinoline-based foldamer library, we have identified a potent foldamer antagonist (SK-131) of Aβ42 aggregation. SK-131 inhibits the aggregation by inducing a α-helical structure in monomeric Aβ42. Here, we demonstrated that SK-131 rescues Aβ42 aggregation-associated phenotypes in AD cellular and multiple Caenorhabditis elegans AD models, including intracellular inhibition of Aβ42 aggregation, rescue of behavioral deficits, and attenuation of reactive oxygen species. It efficiently crosses the blood-brain barrier and demonstrates favorable pharmaceutical properties. It also potently inhibits Zn2+-mediated Aβ42 aggregation by potentially displacing Zn2+ from Aβ42. In summary, we have identified a potent brain-penetrating foldamer that efficiently rescues AD phenotypes in in vivo models. Unlike most of the therapeutic approaches that target Aβ aggregates, we have identified and validated a novel therapeutic pathway by inducing structural change in Aβ and rescuing AD phenotypes in in vivo models. This study will further aid in the quest to identify lead therapeutics to slow or stop the progression of AD.

Alzheimer’s disease (AD) is a progressive pathologythatis linked to abrupt aggregation of amyloid β1–42 (Aβ1–42) peptide in the central nervoussystem. Aβ1–42 aggregation yields amyloidoligomers and fibrils, toxic protein aggregates that cause progressiveneuronal degeneration in the frontal lobe of the brain. Although neuronsremain the focus of AD for decades, a growing body of evidence suggeststhat the degeneration of immune cells in the brain can be the majorcause of AD. However, the extent to which Aβ1–42 aggregates are toxic to the major classes of immune cells in thebrain remains unclear. In the current study, we examine the cytotoxiceffects of Aβ1–42 fibrils on macrophages,dendritic cells, and microglia. These cells play vitally importantroles in development and homeostasis of the central nervous system.We found that Aβ1–42 fibrils caused calciumrelease and enhanced levels of reactive oxygen species in macrophages,dendritic cells, and microglia as well as neurons. We also investigatedthe extent to which the lysozymes of these immune cells could alterthe aggregation properties of Aβ1–42. Ourresults showed that lysosomes extracted from macrophages, dendriticcells, and microglia drastically accelerated Aβ1–42 aggregation as well as altered cytotoxicity of these protein aggregates.These results indicate that impairment of immune cells in the braincan be a critically important aspect of neurodegenerative processesthat are taking place upon the onset of AD.

Bri2 BRICHOS, a folded domain of the transmembrane protein Bri2 expressed in both the brain and pancreas, is an experimentally known substoichiometric inhibitor of amyloid aggregation. The molecular chaperone effectively delays fibrillization at low molar ratios for both β-amyloid (Aβ) in Alzheimer's disease (AD) and islet amyloid polypeptide (IAPP) in type 2 diabetes (T2D). While discovering effective antiamyloid inhibitors that work at low doses is an appealing strategy to mitigate amyloid toxicity, the molecular mechanism underlying the broad and efficient antiamyloid activity of Bri2 BRICHOS remains unknown. Here, we computationally demonstrated that Bri2 BRICHOS exhibits a stronger binding affinity to fibril seeds than to monomers using atomistic discrete molecular dynamic simulations. By competing with monomers to bind the active elongation sites on newly nucleated, weakly populated fibril seeds, a small amount of Bri2 BRICHOS could block rapid fibril growth via monomer addition. The experimentally observed differential inhibition efficiency against IAPP and Aβ aggregation was found to depend on the relative fibril-binding affinities of the inhibitor compared to those of self-seeding monomers. Our computationally derived determinants for substoichiometric inhibition against amyloid aggregation by Bri2 BRICHOS may inform the future design of potent antiamyloid therapies for AD, T2D, and other amyloid diseases.

Voltage-gated sodium channels are the main targets of antiepileptic drugs, such as sodium valproate (VPA). Single nucleotide polymorphisms (SNPs) in the Nav1.6 isoform (SCN8A) have been reported to be closely associated with motor dysfunction in pediatric akathisia epileptica. In this study, we conducted a genetic screening of pediatric patients with seizures treated solely with VPA and identified two novel missense mutations of SCN8A (A1534V and Q1853H). Electrophysiological results revealed that the peak currents of the A1534V variant were smaller compared to that of the wild-type (WT) channel. The A1534V variant also caused a positive shift in the I-V curve, indicating a change in the voltage dependence of activation compared to the WT channels. In contrast, VPA induced a significant negative shift in the inactivation of both WT and A1534V mutant. However, the inhibition of currents by VPA was weaker in the A1534V variant than in WT. Furthermore, the recovery time constant of the A1534V variant was shorter than that of WT when treated with VPA. Regrettably, although the Q1853H variant can be expressed in HEK293T cells, the detected current is too small (approximately 50 pA). In conclusion, our results suggest that the A1534V mutation is a novel loss-of-function variant that exhibits moderate insensitivity to VPA. These results underscore the importance of Nav1.6 as a key target in epilepsy and highlight the necessity of analyzing its role in the pathological process.

Corilagin has shown neuroprotective potential in various neurological disorders, but its effects in Parkinson's disease (PD) have not been fully explored. In this study, we investigated the therapeutic impact and underlying mechanism of corilagin on PD using MPTP-induced mice and MPP+-treated N2a cells. Behavioral tests and immunohistochemical analysis demonstrated that corilagin significantly reduced MPTP-induced loss of TH-positive neurons in the substantia nigra. In vitro, corilagin improved cell viability, decreased MPP+-induced apoptosis, and mitigated the associated oxidative stress by lowering intracellular ROS levels and preserving mitochondrial membrane potential. Moreover, corilagin reversed MPP+-induced iron accumulation and lipid peroxidation in N2a cells. Mechanistically, Western blotting revealed that the protective effects of corilagin are linked to the TLR4/Src/NOX2 signaling pathway. The TLR4 agonist RS 09 impaired the neuroprotective effects of corilagin, further supporting its role in modulating ferroptosis via this pathway. These findings suggest that corilagin could be a promising therapeutic agent for PD by targeting the TLR4/Src/NOX2 signaling axis to inhibit ferroptosis.

Measuring the transduction of electrical signals within neurons is a key capability in neuroscience. Fluorescent voltage sensitive dyes (VSDs) were early tools that complemented classical electrophysiology by enabling the optical recording of membrane potential changes from many cells simultaneously. Recent advances in the VSD field have led to bright and highly sensitive sensors that can be targeted to the desired cell populations in live brain tissue. Despite this progress, recently, protein-based genetically encoded voltage indicators (GEVIs) have become the goto tools for targeted voltage imaging in complex environments. In this Perspective, we summarize progress in developing targetable VSDs, discuss areas where these synthetic sensors are or could become relevant, and outline hurdles that need to be overcome to promote the routine use of targetable VSDs in neuroscience research.

This study investigated the synthesis, characterization, and in silico analysis of novel N-acetamide ketamine derivatives aimed at evaluating their analgesic, anesthetic, and antidepressant properties. The synthesis commenced with the preparation of chloroacetylamide derivatives, which were subsequently reacted with ketamine hydrochloride, yielding 16 derivatives k1 to k16. These compounds were characterized through H1 NMR, C13 NMR, mass spectroscopy (EIMS), and elemental analysis, followed by an assessment of their physicochemical properties. The analgesic efficacy of all of the synthesized derivatives was evaluated using the acetic acid-induced writhing test via intraperitoneal administration. The best-performing molecule was further evaluated for analgesic (acetic acid-induced writhing test, tail suspension test (TST), and hot plate test) and anti-inflammatory (carrageenan-induced paw edema) activities. For antidepressant effects, all derivatives were compared with ketamine in a lipopolysaccharide-induced model of depression in mice through the forced swimming test, open field test (OFT), sucrose preference test (SPT), and TST. It was observed that among all the derivatives, molecule k1 demonstrated comparable analgesic activity to ketamine. Further, compound k1 also exhibited the highest antidepressant potential during the forced swimming test, OFT, SPT, and TST. k1 was further compared with ketamine for their activities intraperitoneally and orally where k1 exhibited comparable antidepressant effects to ketamine. Henceforth, the psychomimetic potential of k1 was evaluated through loss of righting reflex and Y-maze tests. Very interestingly, these tests indicated approximately no psychomimetic activity of k1 compared to ketamine intraperitoneally and orally. Finally, molecular docking studies were conducted targeting the NMDA receptor at the JC09 ketamine binding pocket (PDB ID: 7EU7), where all synthesized derivatives exhibited significant binding affinities relative to ketamine. These findings suggest that the newly synthesized N-acetamide ketamine derivative k1 possesses promising pharmacological profiles, warranting further exploration.

This study investigated the therapeutic potential of exosomes from human umbilical cord mesenchymal stem cells (huMSCs), focusing on PTEN-induced kinase 1 (PINK1) and its impact on exosome efficacy. Postmodification, exosomes were administered to a murine model of intracranial hemorrhage (ICH). Assessments included brain edema, neurological function, anxiety-like behaviors, inflammatory responses, and microglial polarization. We observed that administration of exosomes from control huMSCs significantly reduced brain water content, indicating a reduction in brain edema, as quantitatively assessed through water content analysis. Neurological function, evaluated using a standard scoring system, showed marked improvement in animals treated with control exosomes compared with those receiving PINK1-deficient exosomes, highlighting the importance of PINK1 in mediating neurological recovery. Additionally, control exosomes substantially decreased anxiety-like behaviors in the Open Field Test, demonstrated by reduced immobility times and increased exploratory behavior. Inflammatory response assessments showed a favorable shift with decreased levels of pro-inflammatory cytokines (MCP-1, IL-1β, TNF-α) and increased levels of the anti-inflammatory cytokine IL-10 in the exosome-treated groups. Furthermore, analysis of microglial polarization revealed a shift toward the anti-inflammatory M2 phenotype, evidenced by decreased M1 markers (Cd86, Iba1) and increased M2 markers (Arg1, Cd206) in the control exosome-treated group. Taken together, we found that PINK1-deficient exosomes showed reduced therapeutic efficacy in ICH treatment compared with the exosomes with normal PINK1 expression. Our findings underscore the critical role of PINK1 in enhancing the therapeutic potential of huMSC-derived exosomes in ICH treatment.