Neuronal Function Research Articles

Magnetic targeting enhances the neuroprotective function of human mesenchymal stem cell-derived iron oxide exosomes by delivering miR-1228-5p

BackgroundTreating mitochondrial dysfunction is a promising approach for the treatment of post-stroke cognitive impairment (PSCI). HuMSC-derived exosomes (H-Ex) have shown powerful therapeutic effects in improving mitochondrial function, but the specific effects are unclear and its brain tissue targeting needs to be further optimized.ResultsIn this study, we found that H-Ex can improve mitochondrial dysfunction of neurons and significantly enhance the cognitive behavior performance of MCAO mice in OGD/R-induced SHSY5Y cells and MCAO mouse models. Based on this, we have developed an exosome delivery system loaded with superparamagnetic iron oxide nanoparticles (Spion-Ex) that can effectively penetrate the blood-brain barrier (BBB). The research results showed that under magnetic attraction, Spion-Ex can more effectively target the brain tissue and significantly improve mitochondrial function of neurons after stroke. Meanwhile, we further confirmed that miR-1228-5p is a key factor for H-Ex to improve mitochondrial function and cognitive behavior both in vivo and in vitro. The specific mechanism is that the increase of miR-1228-5p mediated by H-Ex can inhibit the expression of TRAF6 and activate the TRAF6-NADPH oxidase 1 (NOX1) pathway, thereby exerting protective effects against oxidative damage. More importantly, we found that under magnetic attraction, Spion-Ex exhibited excellent cognitive improvement effects by delivering miR-1228-5p.ConclusionsOur research found that H-Ex has a good therapeutic effect on PSCI by increasing the expression of miR-1228-5p in PSCI, while H-Ex loaded with Spion-Ex exhibited more excellent effects on improving mitochondrial function and cognitive impairment under magnetic attraction, which can be used as a novel strategy for the treatment of PSCI.

Dynamic Expression of Genes Encoding Ubiquitin Conjugating Enzymes (E2s) During Neuronal Differentiation and Maturation: Implications for Neurodevelopmental Disorders and Neurodegenerative Diseases

Background: The ubiquitination process plays a crucial role in neuronal differentiation and function. Numerous studies have focused on the expression and functions of E3 ligases during these different stages, far fewer on E2 conjugating enzymes. In mice, as in humans, these E2s belong to 17 conjugating enzyme families. Objectives: We analyzed by real-time PCR the expression dynamics of all known E2 genes during an in vitro differentiation of mouse hippocampal neuronal cultures, and after, we analyzed their stimulation with N-methyl-D-aspartate (NMDA). Results: We found that 36 of the 38 E2 genes were expressed in hippocampal neurons. Many were up-regulated during neuritogenesis and/or synaptogenesis stages, such as Ube2h, Ube2b, and Aktip. Rapid and delayed responses to NMDA stimulation were associated with the increased expression of several E2 genes, such as Ube2i, the SUMO-conjugating E2 enzyme. We also observed similar expression profiles within the same E2 gene family, consistent with the presence of similar transcription factor binding sites in their respective promoter sequences. Conclusions: Our study indicates that specific expression profiles of E2 genes are correlated with changes in neuronal differentiation and activity. A better understanding of the regulation and function of E2s is needed to better understand the role played by the ubiquitination process in physiological mechanisms and pathophysiological alterations involved in neurodevelopmental or neurodegenerative diseases.

Exploring the Dynamic Changes of Brain Lipids, Lipid Rafts, and Lipid Droplets in Aging and Alzheimer’s Disease

Aging induces complex changes in the lipid profiles across different areas of the brain. These changes can affect the function of brain cells and may contribute to neurodegenerative diseases such as Alzheimer’s disease. Research shows that while the overall lipid profile in the human brain remains quite steady throughout adulthood, specific changes occur with age, especially after the age of 50. These changes include a slow decline in total lipid content and shifts in the composition of fatty acids, particularly in glycerophospholipids and cholesterol levels, which can vary depending on the brain region. Lipid rafts play a crucial role in maintaining membrane integrity and facilitating cellular signaling. In the context of Alzheimer’s disease, changes in the composition of lipid rafts have been associated with the development of the disease. For example, alterations in lipid raft composition can lead to increased accumulation of amyloid β (Aβ) peptides, contributing to neurotoxic effects. Lipid droplets store neutral lipids and are key for cellular energy metabolism. As organisms age, the dynamics of lipid droplets in the brain change, with evidence suggesting a decline in metabolic activity over time. This reduced activity may lead to an imbalance in lipid synthesis and mobilization, contributing to neurodegenerative processes. In model organisms like Drosophila, studies have shown that lipid metabolism in the brain can be influenced by diet and insulin signaling pathways, crucial for maintaining metabolic balance. The interplay between lipid metabolism, oxidative stress, and inflammation is critical in the context of aging and Alzheimer’s disease. Lipid peroxidation, a consequence of oxidative stress, can lead to the formation of reactive aldehydes that further damage neurons. Inflammatory processes can also disrupt lipid metabolism, contributing to the pathology of AD. Consequently, the accumulation of oxidized lipids can affect lipid raft integrity, influencing signaling pathways involved in neuronal survival and function.

Diverse Roles of the LINC Complex in Cellular Function and Disease in the Nervous System.

The linker of nucleoskeleton and cytoskeleton (LINC) complex, which spans the nuclear envelope, physically connects nuclear components to the cytoskeleton and plays a pivotal role in various cellular processes, including nuclear positioning, cell migration, and chromosomal configuration. Studies have revealed that the LINC complex is essential for different aspects of the nervous system, particularly during development. The significance of the LINC complex in neural lineage cells is further corroborated by the fact that mutations in genes associated with the LINC complex have been implicated in several neurological diseases, including neurodegenerative and psychiatric disorders. In this review, we aimed to summarize the expanding knowledge of LINC complex-related neuronal functions and associated neurological diseases.

Unraveling the thrombin–Alzheimer’s connection: Oral anticoagulants as potential neuroprotective therapeutics

In Alzheimer’s disease (AD), toxic amyloids formed by amyloid-β (Aβ) proteins and tau are implicated in the development of inflammatory, vascular, and neurodegenerative brain disorders. Thrombin has also been recognized as a proteopathic factor involved in Aβ-induced neurovascular dysfunction. Vascular Aβ activates the contact system in the blood, stimulating the production of inflammatory bradykinin and procoagulant thrombin. Thrombin, in turn, triggers inflammation, platelet activation, and the formation of fibrinolysis-resistant, Aβ-containing fibrin clots, leading to Aß-type cerebral amyloid angiopathy and associated neuropathology. Targeting thrombin with oral anticoagulants can normalize proinflammatory and prothrombotic states, counteracting the neurovascular consequences of AD. Pre-clinical studies have shown that such interventions preserve vascular and blood–brain barrier integrity, improve cerebral blood flow and brain perfusion, and reduce parenchymal accumulations of toxic Aβ, tau, fibrin(ogen), and thrombin. These effects mitigate neuroinflammatory and neurodegenerative processes, ultimately preserving cognitive functions for a longer period. Recent observational clinical studies in patients with atrial fibrillation (AF) demonstrated that treatment with direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs) reduced the risk of dementia by up to 48% compared to non-users. The anti-dementia effects were most prominent in elderly patients but were also observed in individuals with low AF risk or newly diagnosed AF. In addition, DOACs reduced the risk of intracranial hemorrhage by approximately 50% compared to VKAs. The current review highlights the potential neuroprotective role of DOACs in AD. By preventing excessive thrombin generation caused by Aβ pathology, DOACs could protect vascular and neuronal functions, thereby slowing cognitive decline. DOACs, such as dabigatran, apixaban, and rivaroxaban, warrant further clinical investigation for their potential repurposing as disease-modifying therapeutics in AD.

Mouse enteric neurons control intestinal plasmacytoid dendritic cell function via serotonin-HTR7 signaling

Serotonergic neurons in the central nervous system control behavior and mood, but knowledge of the roles of serotonergic circuits in the regulation of immune homeostasis is limited. Here, we employ mouse genetics to investigate the functions of enteric serotonergic neurons in the control of immune responses and find that these circuits regulate IgA induction and boost host defense against oral, but not systemic Salmonella Typhimurium infection. Enteric serotonergic neurons promote gut-homing, retention and activation of intestinal plasmacytoid dendritic cells (pDC). Mechanistically, this neuro-immune crosstalk is achieved through a serotonin-5-HT receptor 7 (HTR7) signaling axis that ultimately facilitates the pDC-mediated differentiation of IgA+ B cells from IgD+ precursors in the gut. Single-cell RNA-seq data further reveal novel patterns of bidirectional communication between specific subsets of enteric neurons and lamina propria DC. Our findings thus reveal a close interplay between enteric serotonergic neurons and gut immune homeostasis that enhances mucosal defense.

Aberrance of GAP43/p-GAP43 Closely Associates with the Pathology of Neuron Loss in Prion-Infected Rodent Models.

Prion diseases are fatal neurodegenerative disorders characterized by neuron damage and loss. Growth-associated protein 43 (GAP43) functions in neuronal plasticity and synaptic function, but its role in prion diseases is not fully elucidated. In this study, we investigated the changes of GAP43 in the central nerve system (CNS) of several prion-infected rodent models and explored the potential relationship of GAP43 with PrPSc deposit and neuron loss using various methods. We found that GAP43 levels were significantly decreased in the brain tissues of scrapie-infected rodent models at the terminal stage of the disease. Immunohistochemical analysis showed that GAP43 colocalized with NeuN-positive cells morphologically, indicating the presence of GAP43 in mature neurons. On contrary, the levels of GAP43 and p-GAP43 increased in a prion-infected cell line SMB-S15 in vitro, accompanying with the increase of intracellular calcium. Stimulation of lipopolysaccharide (LPS) upregulated while removal of PrPSc propagation downregulated the level of GAP43 in SMB-S15 cells. Morphological colocalization and molecular interaction between GAP43 and PrPSc have been addressed in the brains of prion-infected rodents and prion-infected cell line. Histological assays of the serial sections of the whole brains of prion-infected mice proposed that the reduced GAP43 level correlated with large amount of PrPSc deposits and notable neuron damage and loss showing cell crumpled and nuclear pyknosis. The impairment of GAP43 signaling and disturbance of calcium homeostasis by aberrance of brain GAP43/p-GAP43 not only reflect but also likely contribute to the pathology of severe neuron loss at the end of prion disease.

Modulation of autophagy by melatonin and its receptors: implications in brain disorders.

Autophagy plays a crucial role in maintaining neuronal homeostasis and function, and its disruption is linked to various brain diseases. Melatonin, an endogenous hormone that primarily acts through MT1 and MT2 receptors, regulates autophagy via multiple pathways. Growing evidence indicates that melatonin's ability to modulate autophagy provides therapeutic and preventive benefits in brain disorders, including neurodegenerative and affective diseases. In this review, we summarize the key mechanisms by which melatonin affects autophagy and explore its therapeutic potential in the treatment of brain disorders.

Low-Energy extracorporeal shockwave therapy improves locomotor functions, tissue regeneration and modulating the inflammation induced FGF1 and FGF2 signaling to protect damaged tissue in spinal cord injury of rat model: An experimental animal study.

Spinal cord injury (SCI) is a debilitating condition that results in severe motor function impairments. Current therapeutic options remain limited, underscoring the need for novel treatments. Extracorporeal shockwave therapy (ESWT) has emerged as a promising noninvasive approach for treating musculoskeletal disorders and nerve regeneration. This study explored the effects of low-energy ESWT on locomotor function, tissue regeneration, inflammation, and mitochondrial function in a rat SCI model. Experiments were performed using locomotor function assays, CatWalk gait analysis, histopathological examination, immunohistochemical and immunofluorescence staining. The findings demonstrated that low-energy ESWT had a dose-dependent effect, with three treatment sessions (ESWT3) showing superior outcomes compared to a single session. ESWT3 significantly improved motor functions (run patterns, run average speed, and maximum variation, as well as the Basso, Beattie, and Bresnahan (BBB) score) and promoted tissue regeneration while reducing inflammation. ESWT3 significantly decreased levels of IL-1β, IL6 and macrophages (CD68) while increasing leucocyte (CD45) infiltration. Additionally, ESWT3 upregulated NueN and mitofusin 2 (MFN2), suggesting enhanced neuronal health and mitochondrial function. Moreover, ESWT3 modulated the expression of fibroblast growth factor 1 (FGF1), FGF2, their receptor FGFR1 and phosphorylation of ERK, aiding tissue repair and regeneration in SCI. This study highlights the potential of low-energy ESWT as an effective noninvasive treatment for SCI, demonstrating significant improvements in motor recovery, tissue regeneration, anti-inflammatory effects, and mitochondrial protection. These findings provide valuable insights into the mechanisms of ESWT and its therapeutic application for SCI recovery.

Sleep Disorders in Alzheimer’s Disease

Alzheimer’s disease is the leading cause of dementia worldwide. Patients typically exhibit cognitive impairment, memory loss, diminished social and occupational functioning, as well as language and motor disorders. Alzheimer’s disease is characterized by the abnormal accumulation of amyloid-β (Aβ) and phosphorylated tau in the brain. These pathological changes not only disrupt neuronal function and lead to cognitive deficits, but also interfere with sleep regulation, resulting in sleep disorders. Such disturbances can diminish nighttime sleep quality and contribute to daytime functional impairments, further exacerbating cognitive decline. Therefore, exploring the interplay between cognitive impairment, Alzheimer’s disease, and sleep disorders is crucial for enhancing the quality of life of Alzheimer’s patients. This review summarizes current literature on the interconnections among Alzheimer’s disease, cognitive impairment, and sleep disorders. Sleep disturbances are prevalent in Alzheimer’s patients and can also occur in those with amnestic mild cognitive impairment, which often precedes Alzheimer’s onset. Such sleep disorders may promote and accelerate the accumulation of amyloid-β and tau proteins [1-3]. Furthermore, Alzheimer’s patients may be more vulnerable to sleep disturbances, creating a potential vicious cycle. Further investigation into these relationships may provide valuable insights for the treatment or prevention of Alzheimer’s disease.

Omnidirectional improvement of mitochondrial health in Alzheimer's disease by multi-targeting engineered activated neutrophil exosomes

Alzheimer's disease (AD) is one kind of devasting neurodegenerative disorders affecting over 50 million people worldwide. Multi-targeted therapy has emerged as a new treatment for diagnosing and alleviating the pathogenesis process of AD; however, the current strategy is limited by its unsatisfactory efficiency. In our study, engineered activated neutrophil-derived exosomes (MP@Cur-MExo) were developed to improve the mitochondrial function in neurons by targeting and alleviating Aβ-induced neurotoxicity. MP@Cur-MExo are exosomes derived from IL-8-stimulated neutrophils decorated with mitochondria targeting ligand and Aβ targeted ligand modified SPION. Engineered exosomes can be cleaved by matrix metallopeptidase-2, which is overexpressed in the AD brain. Consequently, the released SPION and Curcumin-loaded engineered exosomes collaboratively protected neuron cells against Aβ-induced mitochondrial deficiency. In addition, MP@Cur-MExo effectively accumulated in the inflamed region of AD brain at an early stage, allowing early diagnosis of AD through bimodal (MRI/IVIS) imaging. Importantly, in a mouse model at an early stage of AD, intravenously injected MP@Cur-MExo restored mitochondrial function and reduced Aβ-induced mitochondrial damage, thereby attenuating AD progression. In conclusion, our designed engineered exosomes demonstrated that omnidirectional improvement of mitochondrial function can serve as a novel and practical approach for the diagnosis and treatment of neurodegenerative diseases. This study also reveals a promising therapeutic agent for impeding AD progression for future clinical applications.

Atp13a5 Marker Reveals Pericyte Specification in the Mouse Central Nervous System.

Perivascular mural cells including vascular smooth cells (VSMCs) and pericytes are integral components of the vascular system. In the central nervous system (CNS), pericytes are also indispensable for the blood-brain barrier (BBB), blood-spinal cord barrier, and blood-retinal barrier and play key roles in maintaining cerebrovascular and neuronal functions. However, the functional specifications of pericytes between CNS and peripheral organs have not been resolved at the genetic and molecular levels. Hence, the generation of reliable CNS pericyte-specific models and genetic tools remains very challenging. Here, we report a new CNS pericyte marker in mice. This putative cation-transporting ATPase 13A5 (Atp13a5) marker was identified through single-cell transcriptomics, based on its specificity to brain pericytes. We further generated a knock-in model with both tdTomato reporter and Cre recombinase. Using this model to trace the distribution of Atp13a5-positive pericytes in mice, we found that the tdTomato reporter reliably labels the CNS pericytes, including the ones in spinal cord and retina but not peripheral organs. Interestingly, brain pericytes are likely shaped by the developing neural environment, as Atp13a5-positive pericytes start to appear around murine embryonic day 15 (E15) and expand along the cerebrovasculature. Thus, Atp13a5 is a specific marker of CNS pericyte lineage, and this Atp13a5-based model is a reliable tool to explore the heterogeneity of pericytes and BBB functions in health and diseases.

Analog reservoir computing via ferroelectric mixed phase boundary transistors

Analog reservoir computing (ARC) systems have attracted attention owing to their efficiency in processing temporal information. However, the distinct functionalities of the system components pose challenges for hardware implementation. Herein, we report a fully integrated ARC system that leverages material versatility of the ferroelectric-to-mixed phase boundary (MPB) hafnium zirconium oxides integrated onto indium–gallium–zinc oxide thin-film transistors (TFTs). MPB-based TFTs (MPBTFTs) with nonlinear short-term memory characteristics are utilized for physical reservoirs and artificial neuron, while nonvolatile ferroelectric TFTs mimic synaptic behavior for readout networks. Furthermore, double-gate configuration of MPBTFTs enhances reservoir state differentiation and state expansion for physical reservoir and processes both excitatory and inhibitory pulses for neuronal functionality with minimal hardware burden. The seamless integration of ARC components on a single wafer executes complex real-world time-series predictions with a low normalized root mean squared error of 0.28. The material-device co-optimization proposed in this study paves the way for the development of area- and energy-efficient ARC systems.

Neuronal SLC39A8 deficiency impairs cerebellar development by altering manganese homeostasis.

Solute carrier family 39, member 8 (SLC39A8), is a transmembrane transporter that mediates the cellular uptake of zinc, iron, and manganese (Mn). Human genetic studies document the involvement of SLC39A8 in Mn homeostasis, brain development, and function. However, the role and pathophysiological mechanisms of SLC39A8 in the central nervous system remain elusive. We generated Slc39a8 neuron-specific knockout (Slc39a8-NSKO) mice to study SLC39A8 function in neurons. The Slc39a8-NSKO mice displayed markedly decreased Mn levels in the whole brain and brain regions, especially the cerebellum. Radiotracer studies using 54Mn revealed that Slc39a8-NSKO mice had impaired brain uptake of Mn. Slc39a8-NSKO cerebellums exhibited morphological defects and abnormal dendritic arborization of Purkinje cells. Reduced neurogenesis and increased apoptotic cell death occurred in the cerebellar external granular layer of Slc39a8-NSKO mice. Brain Mn deficiency in Slc39a8-NSKO mice was associated with motor dysfunction. Unbiased RNA-Seq analysis revealed downregulation of key pathways relevant to neurodevelopment and synaptic plasticity, including cAMP signaling pathway genes. We further demonstrated that Slc39a8 was required for the optimal transcriptional response to the cAMP-mediated signaling pathway. In summary, our study highlighted the essential roles of SLC39A8 in brain Mn uptake and cerebellum development and functions.

NF-κB in Alzheimer's Disease: Friend or Foe? Opposite Functions in Neurons and Glial Cells.

Alzheimer's disease (AD) is a devasting neurodegenerative disease afflicting mainly glutamatergic neurons together with a massive neuroinflammation mediated by the transcription factor NF-κB. A 65%-plus increase in Alzheimer's patients by 2050 might be a major threat to society. Hallmarks of AD are neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau and amyloid beta (Aβ) plaques. Here, we review the potential involvement of transcription factor NF-κB by hereditary mutations of the tumor necrosis factor pathway in AD patients. One of the greatest genetic risk factors is APOE4. Recently, it was shown that the APOE4 allele functions as a null allele in human astrocytes not repressing NF-κB anymore. Moreover, NF-κB seems to be involved in the repair of DNA double-strand breaks during healthy learning and memory, a function blunted in AD. NF-κB could be a friend to healthy neurons by repressing apoptosis and necroptosis. But a loss of neuronal NF-κB and activation of glial NF-κB in AD makes it a foe of neuronal survival. Hopeful therapies include TNFR2 receptor bodies relieving the activation of glial NF-κB by TNFα.

Myeloid-derived β-hexosaminidase is essential for neuronal health and lysosome function: implications for Sandhoff disease.

Lysosomal storage disorders (LSDs) are a large disease class involving lysosomal dysfunction, often resulting in neurodegeneration. Sandhoff disease (SD) is an LSD caused by a deficiency in the β subunit of the β-hexosaminidase enzyme ( Hexb ). Although Hexb expression in the brain is specific to microglia, SD primarily affects neurons. To understand how a microglial gene is involved in maintaining neuronal homeostasis, we demonstrated that β-hexosaminidase is secreted by microglia and integrated into the neuronal lysosomal compartment. To assess therapeutic relevance, we treated SD mice with bone marrow transplant and colony stimulating factor 1 receptor inhibition, which broadly replaced Hexb -/- microglia with Hexb -sufficient cells. This intervention reversed apoptotic gene signatures, improved behavior, restored enzymatic activity and Hexb expression, ameliorated substrate accumulation, and normalized neuronal lysosomal phenotypes. These results underscore the critical role of myeloid-derived β- hexosaminidase in neuronal lysosomal function and establish microglial replacement as a potential LSD therapy.

Evaluation of Alpha-Synuclein and Tau Antiaggregation Activity of Urea and Thiourea-Based Small Molecules for Neurodegenerative Disease Therapeutics.

Alzheimer's disease (AD) and Parkinson's disease (PD) are multifactorial, chronic diseases involving neurodegeneration. According to recent studies, it is hypothesized that the intraneuronal and postsynaptic accumulation of misfolded proteins such as α-synuclein (α-syn) and tau, responsible for Lewy bodies (LB) and tangles, respectively, disrupts neuron functions. Considering the co-occurrence of α-syn and tau inclusions in the brains of patients afflicted with subtypes of dementia and LB disorders, the discovery and development of small molecules for the inhibition of α-syn and tau aggregation can be a potentially effective strategy to delay neurodegeneration. Urea is a chaotropic agent that alters protein solubilization and hydrophobic interactions and inhibits protein aggregation and precipitation. The presence of three hetero atoms (O/S and N) in proximity can coordinate with neutral, mono, or dianionic groups to form stable complexes in the biological system. Therefore, in this study, we evaluated urea and thiourea linkers with various substitutions on either side of the carbamide or thiocarbamide functionality to compare the aggregation inhibition of α-syn and tau. A thioflavin-T (ThT) fluorescence assay was used to evaluate the level of fibril formation and monitor the anti-aggregation effect of the different compounds. We opted for transmission electron microscopy (TEM) as a direct means to confirm the anti-fibrillar effect. The oligomer formation was monitored via the photoinduced cross-linking of unmodified proteins (PICUP). The anti-inclusion and anti-seeding activities of the best compounds were evaluated using M17D intracellular inclusion and biosensor cell-based assays, respectively. Disaggregation experiments were performed with amyloid plaques extracted from AD brains. The analogues with indole, benzothiazole, or N,N-dimethylphenyl on one side with halo-substituted aromatic moieties had shown less than 15% cutoff fluorescence obtained with the ThT assay. Our lead molecules 6T and 14T reduced α-syn oligomerization dose-dependently based on the PICUP assays but failed at inhibiting tau oligomer formation. The anti-inclusion effect of our lead compounds was confirmed using the M17D neuroblastoma cell model. Compounds 6T and 14T exhibited an anti-seeding effect on tau using biosensor cells. In contrast to the control, disaggregation experiments showed fewer Aβ plaques with our lead molecules (compounds 6T and 14T). Pharmacokinetics (PK) mice studies demonstrated that these two thiourea-based small molecules have the potential to cross the blood-brain barrier in rodents. Urea and thiourea linkers could be further improved for their PK parameters and studied for the anti-inclusion, anti-seeding, and disaggregation effects using transgenic mice models of neurodegenerative diseases.

Disorders of puberty and neurodevelopment: A shared etiology?

The neuroendocrine control of puberty and reproduction is fascinatingly complex, with up- and down-regulation of key reproductive hormones during fetal, infantile, and later childhood periods that determine the correct function of the hypothalamic-pituitary-gonadal axis and the timing of puberty. Neuronal development is a vital element of these processes, and multiple conditions of disordered puberty and reproduction have their etiology in abnormal neuronal migration or function. Although there are numerous documented cases across multiple conditions wherein patients have both neurodevelopmental disorders and pubertal abnormalities, this has mostly been described ad hoc and the associations are not clearly documented. In this review, we aim to describe the overlap between these two groups of conditions and to increase awareness to ensure that puberty and reproductive function are carefully monitored in patients with neurodevelopmental conditions, and vice versa. Moreover, this commonality can be explored for clues about the disease mechanisms in these patient groups and provide new avenues for therapeutic interventions for affected individuals.

Altered Proteasome Composition in Aging Brains, Genetic Proteasome Augmentation Mitigates Age-Related Cognitive Declines, and Acute Proteasome Agonist Treatment Rescues Age-Related Cognitive Deficits in Mice.

The aging brain experiences a significant decline in proteasome function, The proteasome is critical for many key neuronal functions including neuronal plasticity, and memory formation/retention. Treatment with proteasome inhibitors impairs these processes. Our study reveals a marked reduction in 20S and 26S proteasome activities in aged mice brains driven by reduced functionality of aged proteasome. This is matched by a decline in 20S proteasome but an increase in 26S proteasome. Our data suggests this may be a compensatory response to reduced functionality. By overexpressing the proteasome subunit PSMB5 in the neurons of mice, enhancing proteasome function, we slowed age-related declines in spatial learning and memory as well neuromuscular declines. We then showed acute treatment with a proteasome activator to rescue spatial learning and memory deficits in aged mice. These findings highlight the potential of proteasome augmentation as a therapeutic strategy to mitigate age-related cognitive declines.

Growth Factor Gene Therapy for Alzheimer's Disease.

Nervous system growth factors are natural proteins of the brain that influence neuronal survival and function throughout life, from embryonic development to old age. In animal models of Alzheimer's disease (AD), the growth factor brain derived neurotrophic factor (BDNF) prevents neuronal death, activates neuronal function, builds new synapses and improves learning and memory. Accordingly, we are determining whether gene delivery of BDNF in patients with AD will slow disease progression and improve memory. In a previous clinical trial of nerve growth factor (NGF) gene therapy in AD patients (NCT00017940, June 2001), we learned that growth factors can unequivocally elicit classic trophic responses from degenerating neurons in AD. Experience gained from the earlier NGF gene therapy trial is guiding our effort to optimize gene delivery of BDNF in our present clinical program (NCT05040217, June 2021).