Memory Defects Research Articles

Rosmarinus officinalis extract ameliorates cognitive deficits and hippocampal neurogenesis in mice model of diabetes mellitus

RationaleDiabetes mellitus causes cognitive impairment and negatively affects the hippocampal integrity and neurogenesis. The impaired insulin activity and secretion contribute to the down-regulation of fibroblast growth factor which is an important stimulant of the neurogenic process. The present study elucidated the potential effects of Rosmarinus officinalis, (R. officinalis) on spatial memory and adult hippocampal neurogenesis in diabetic mice model using behavioral tests, histological and immunohistochemical analysis. Material and methodsThe male Balb/c mice were administered a high-fat diet and streptozotocin (STZ) (100 mg/kg i.p.) at 6th and 9th week of age. Following that, 36 h after second dose of STZ, 50 mg/kg R. officinalis extract was administered orally for 21 days. ResultsSTZ and a high-fat diet caused diabetes that led to the defects in learning and memory and compromised the process of hippocampal neurogenesis. Interestingly, R. officinalis improved cognitive functions and increased the expression of neurogenic markers including KI67 and NeuN, suggesting an improvement in the process of adult hippocampal neurogenesis. ConclusionsIt has been suggested that R. officinalis may act as a potential agent for the improvement of neurodegeneration and learning and memory deficits associated with diabetes. These findings warrant further investigation of the specific active constituents of R. officinalis involved in the regulation of these molecular processes to be considered as novel adjunctive therapy for diabetes mellitus-associated neurological consequences.

Role of Cytoskeletal Elements in Regulation of Synaptic Functions: Implications Toward Alzheimer's Disease and Phytochemicals-Based Interventions.

Alzheimer's disease (AD), a multifactorial disease, is characterized by the accumulation of neurofibrillary tangles (NFTs) and amyloid beta (Aβ) plaques. AD is triggered via several factors like alteration in cytoskeletal proteins, a mutation in presenilin 1 (PSEN1), presenilin 2 (PSEN2), amyloid precursor protein (APP), and post-translational modifications (PTMs) in the cytoskeletal elements. Owing to the major structural and functional role of cytoskeletal elements, like the organization of axon initial segmentation, dendritic spines, synaptic regulation, and delivery of cargo at the synapse; modulation of these elements plays an important role in AD pathogenesis; like Tau is a microtubule-associated protein that stabilizes the microtubules, and it also causes inhibition of nucleo-cytoplasmic transportation by disrupting the integrity of nuclear pore complex. One of the major cytoskeletal elements, actin and its dynamics, regulate the dendritic spine structure and functions; impairments have been documented towards learning and memory defects. The second major constituent of these cytoskeletal elements, microtubules, are necessary for the delivery of the cargo, like ion channels and receptors at the synaptic membranes, whereas actin-binding protein, i.e., Cofilin's activation form rod-like structures, is involved in the formation of paired helical filaments (PHFs) observed in AD. Also, the glial cells rely on their cytoskeleton to maintain synaptic functionality. Thus, making cytoskeletal elements and their regulation in synaptic structure and function as an important aspect to be focused for better management and targeting AD pathology. This review advocates exploring phytochemicals and Ayurvedic plant extracts against AD by elucidating their neuroprotective mechanisms involving cytoskeletal modulation and enhancing synaptic plasticity. However, challenges include their limited bioavailability due to the poor solubility and the limited potential to cross the blood-brain barrier (BBB), emphasizing the need for targeted strategies to improve therapeuticefficacy.

Antioxidative Effects of Hydro-Alcoholic Extract and Essential Oil of Quercus brantii Exerts Anti-Depressant-Like Effect and Improvement of Memory Defect in Progesterone-Induced Postpartum Depression in Rats

Background: Depression and memory disorders are known to be associated with increased oxidative stress. There is evidence suggesting that Quercus brantii (Q. brantii) possesses antioxidant properties. Objectives: This study aims to investigate the impact of Q. brantii hydro-alcoholic extract and oil on cognitive dysfunction in a postpartum depression (PPD) model and on oxidant/antioxidant activity in the hippocampus of adult female rats. Methods: Forty-two female Wistar rats (200 - 250 g) were randomly divided into six groups. PPD was induced by chronic intraperitoneal administration (5 days) of progesterone at a dose of 5 mg/kg, and three days after discontinuation, depressive behavior was assessed using a forced swimming test. Simultaneously, Quercus brantii hydro-alcoholic extract (100 mg/kg) and oil (45%) were administered. Spatial memory and locomotor activity were evaluated 24 hours after training using the Morris water maze and open field tests, respectively. The hippocampus tissue of all rats was used to evaluate oxidant-antioxidant factors, Vitamin D, and corticosterone levels. Results: Quercus brantii extract significantly reduced depression (P < 0.05). Treatment with Q. brantii extract and oil improved spatial memory and learning (P < 0.05). The Q. brantii extract increased levels of SOD, GSH, catalase, and vitamin D while decreasing MDA levels; additionally, Q. brantii oil increased SOD and vitamin D levels and decreased MDA levels in the brain (P < 0.05). Conclusions: Quercus brantii extract and oil appear to have beneficial effects on learning and memory impairment in a PPD-induced model, which may be associated with their biochemical effects on the brain.

Aging-induced tRNAGlu-derived fragment impairs glutamate biosynthesis by targeting mitochondrial translation-dependent cristae organization

Mitochondrial cristae, infoldings of the mitochondrial inner membrane, undergo aberrant changes in their architecture with age. However, the underlying molecular mechanisms and their contribution to brain aging are largely elusive. Here, we observe an age-dependent accumulation of Glu-5'tsRNA-CTC, a transfer-RNA-derived small RNA (tsRNA), derived from nuclear-encoded tRNAGlu in the mitochondria of glutaminergic neurons. Mitochondrial Glu-5'tsRNA-CTC disrupts the binding of mt-tRNALeu and leucyl-tRNA synthetase2 (LaRs2), impairing mt-tRNALeu aminoacylation and mitochondria-encoded protein translation. Mitochondrial translation defects disrupt cristae organization, leading to damaged glutaminase (GLS)-dependent glutamate formation and reduced synaptosomal glutamate levels. Moreover, reduction of Glu-5'tsRNA-CTC protects aged brains from age-related defects in mitochondrial cristae organization, glutamate metabolism, synaptic structures, and memory. Thus, beyond illustrating a physiological role for normal mitochondrial cristae ultrastructure in maintaining glutamate levels, our study defines a pathological role for tsRNAs in brain aging and age-related memory decline.

New aspects of a small GTPase RAB35 in brain development and function.

In eukaryotic cells, organelles in the secretory, lysosomal, and endocytic pathways actively exchange biological materials with each other through intracellular membrane trafficking, which is the process of transporting the cargo of proteins, lipids, and other molecules to appropriate compartments via transport vesicles or intermediates. These processes are strictly regulated by various small GTPases such as the RAS-like in rat brain (RAB) protein family, which is the largest subfamily of the RAS superfamily. Dysfunction of membrane trafficking affects tissue homeostasis and leads to a wide range of diseases, including neurological disorders and neurodegenerative diseases. Therefore, it is important to understand the physiological and pathological roles of RAB proteins in brain function. RAB35, a member of the RAB family, is an evolutionarily conserved protein in metazoans. A wide range of studies using cultured mammalian cells and model organisms have revealed that RAB35 mediates various processes such as cytokinesis, endocytic recycling, actin bundling, and cell migration. RAB35 is also involved in neurite outgrowth and turnover of synaptic vesicles. We generated brain-specific Rab35 knockout mice to study the physiological roles of RAB35 in brain development and function. These mice exhibited defects in anxiety-related behaviors and spatial memory. Strikingly, RAB35 is required for the precise positioning of pyramidal neurons during hippocampal development, and thereby for normal hippocampal lamination. In contrast, layer formation in the cerebral cortex occurred superficially, even in the absence of RAB35, suggesting a predominant role for RAB35 in hippocampal development rather than in cerebral cortex development. Recent studies have suggested an association between RAB35 and neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. In this review, we provide an overview of the current understanding of subcellular functions of RAB35. We also provide insights into the physiological role of RAB35 in mammalian brain development and function, and discuss the involvement of RAB35 dysfunction in neurodegenerative diseases.

Exploring the anti-ferroptosis mechanism of Kai-Xin-San against Alzheimer's disease through integrating network pharmacology, bioinformatics, and experimental validation strategy in vivo and in vitro

Ethnopharmacological relevanceKai Xin San (KXS), first proposed by Sun Simiao during the Tang Dynasty, has been utilized to treat dementia by tonifying qi and dispersing phlegm. Aim of the studyThis study aimed to elucidate the mechanism by which KXS exerts its therapeutic effects on Alzheimer's disease (AD) by targeting ferroptosis, using a combination of network pharmacology, bioinformatics, and experimental validation strategies. Materials and methodsThe active target sites and the further potential mechanisms of KXS in protecting against AD were investigated through molecular docking, molecular dynamics simulation, and network pharmacology, and combined with the validation of animal experiments. ResultsComputational and experimental findings provide the first indication that KXS significantly improves learning and memory defects and inhibits neuronal ferroptosis by repairing mitochondria damage and upregulating the protein expression of ferroptosis suppressor protein 1 (FSP1) in vivo APP/PS1 mice AD model. According to bioinformatics analysis, the mechanism by which KXS inhibits ferroptosis may involve SIRT1. KXS notably upregulated the mRNA and protein expression of SIRT1 in both vivo APP/PS1 mice and in vitro APP-overexpressed HT22 cells. Additionally, KXS inhibited ferroptosis induced by APP-overexpression in HT22 cells through activating the SIRT1-FSP1 signal pathway. ConclusionsCollectively, our findings suggest that KXS may inhibit neuronal ferroptosis through activating the SIRT1/FSP1 signaling pathway. This study reveals the scientific basis and underlying modern theory of replenishing qi and eliminating phlegm, which involves the inhibition of ferroptosis. Moreover, it highlights the potential application of SIRT1 or FSP1 activators in the treatment of AD and other ferroptosis-related diseases.

RNF220-mediated K63-linked polyubiquitination stabilizes Olig proteins during oligodendroglial development and myelination.

Maldevelopment of oligodendroglia underlies neural developmental disorders such as leukodystrophy. Precise regulation of the activity of specific transcription factors (TFs) by various posttranslational modifications (PTMs) is required to ensure proper oligodendroglial development and myelination. However, the role of ubiquitination of these TFs during oligodendroglial development is yet unexplored. Here, we find that RNF220, a known leukodystrophy-related E3 ubiquitin ligase, is required for oligodendroglial development. RNF220 depletion in oligodendrocyte lineage cells impedes oligodendrocyte progenitor cell proliferation, differentiation, and (re)myelination, which consequently leads to learning and memory defects. Mechanistically, RNF220 targets Olig1/2 for K63-linked polyubiquitination and stabilization during oligodendroglial development. Furthermore, in a knock-in mouse model of leukodystrophy-related RNF220R365Q mutation, the ubiquitination and stabilization of Olig proteins are deregulated in oligodendroglial cells. This results in pathomimetic oligodendroglial developmental defects, impaired myelination, and abnormal behaviors. Together, our evidence provides an alternative insight into PTMs of oligodendroglial TFs and how this essential process may be implicated in the etiology of leukodystrophy.

Comparison of retrospective and prospective memory in subtypes of obsessive-compulsive disorder.

Retrospective and prospective memory deficits play a role in maintaining and perpetuating the symptoms of obsessive-compulsive disorder (OCD), but less is known about these deficits in different subtypes of OCD. The aim of the present study was to evaluate the retrospective and prospective memory in patients suffering from cleaning, checking, symmetry, and religious obsessions. In a comparative causal method, 60 participants aged 28 to 55, in 2023, were selected by convenience sampling and placed in five groups of individuals with cleaning, checking, symmetry, religious obsessions, and a healthy group. Participants completed self-report questionnaires and neurocognitive tools. Results showed that defects in retrospective memory were significant in all types of obsessions (p<0.05) except religious obsessions. Also, this defect was more severe in checking obsession disorder compared to other types of OCD. Also, the finding indicated that the defect in prospective memory was significant only in checking obsession disorder (p<0.05). Retrospective and prospective memory impairments and their relationship with deficits in executive functions can be different depending on the type of OCD. Based on the findings, impairment of executive function indirectly by impacting the impairment of other cognitive mechanisms diminishes confidence in retrospective and prospective memory which leads to compulsive behaviors in individuals with contamination and checking obsessions. Also, the impairment of retrospective memory in symmetry obsessions might have a relationship with information encoding, which in turn leads to difficulty recalling information from memory.

Herbal Medicine: A Promising Approach for the Treatment of Alzheimer's Disease

Alzheimer's disease is a progressive neurodegenerative disease manifesting in cognitive decline, impairment of memory, and behavioural deterioration. Alzheimer’s is a relatively common type of dementia. The pathological basis for the progression of Alzheimer's disease is beta-amyloid protein accumulation, phosphorylation of tau protein, abnormal glial cell function, inflammation, neurotransmitter imbalance, along with oxidative stress in brain tissue. Current available therapies are targeted at amelioration of symptoms alone and focus on a limited spectrum of pathophysiological processes. It is evident that it is essential to develop a multi-target therapeutic option in managing Alzheimer's disease, in view of the broad range of factors in disease progression and sever consequences for sufferers. Herbal medicines are seen as a potential resource in the treatment of Alzheimer's disease, in view of their historical use in traditional medicine as neuroprotectants. Herbal medicines have been evaluated in animal studies designed to determine their capacity to prevent neurodegenerative disease and ameliorate memory defects. This review elaborates on the studies conducted on several medicinal plants that have been investigated for their potential in the prevention and treatment of memory defects in animal models.

Pasteurized Akkermansia muciniphila improves irritable bowel syndrome-like symptoms and related behavioral disorders in mice

ABSTRACT Gut – brain communications disorders in irritable bowel syndrome (IBS) are associated with intestinal microbiota composition, increased gut permeability, and psychosocial disturbances. Symptoms of IBS are difficult to medicate, and hence much research is being made into alternative approaches. This study assesses the potential of a treatment with pasteurized Akkermansia muciniphila for alleviating IBS-like symptoms in two mouse models of IBS with different etiologies. Two clinically relevant animal models were used to mimic IBS-like symptoms in C57BL6/J mice: the neonatal maternal separation (NMS) paradigm and the Citrobacter rodentium infection model. In both models, gut permeability, colonic sensitivity, fecal microbiota composition and colonic IL-22 expression were evaluated. The cognitive performance and emotional state of the animals were also assessed by several tests in the C. rodentium infection model. The neuromodulation ability of pasteurized A. muciniphila was assessed on primary neuronal cells from mice dorsal root ganglia using a ratiometric calcium imaging approach. The administration of pasteurized A. muciniphila significantly reduced colonic hypersensitivity in both IBS mouse models, accompanied by a reinforcement of the intestinal barrier function. Beneficial effects of pasteurized A. muciniphila treatment have also been observed on anxiety-like behavior and memory defects in the C. rodentium infection model. Finally, a neuroinhibitory effect exerted by pasteurized A. muciniphila was observed on neuronal cells stimulated with two algogenic substances such as capsaicin and inflammatory soup. Our findings demonstrate novel anti-hyperalgesic and neuroinhibitory properties of pasteurized A. muciniphila, which therefore may have beneficial effects in relieving pain and anxiety in subjects with IBS.

PKCε activator protects hippocampal microvascular disruption and memory defect in 3×Tg-Alzheimer's disease mice with cerebral microinfarcts.

Current evidence suggests that microvessel disease is involved in Alzheimer's disease (AD). Cerebrovascular disease correlates with cardiovascular disease and is complicated in ≈40% of AD patients. The protein kinase C (PKC) ε activator DCPLA can stimulate human antigen (Hu) R that prevents degradation and promotes the translation of mitochondrial Mn-superoxide dismutase (MnSOD) and vascular endothelial growth factor-A (VEGF) mRNAs. To induce brain microinfarcts, we injected triple transgenic (3×Tg) and wild-type (WT) control mice with microbeads (20 μm caliber) into common carotid arteries, with or without the DCPLA-ME (methyl-ester) for 2 weeks. After water maze training, mice at 16 months old were examined for confocal immunohistochemistry at a single cell or microvessel level in the hippocampal CA1 area, important for spatial memory storage, and in the dorsal hippocampus by western blots. In 3×Tg mice without cerebral microinfarcts, an accelerating age-related increase in (mild) oxidative stress and hypoxia inducible factor (HIF)-1α, but a reduction in VEGF, mitochondrial transcription factor A (TFAM), and MnSOD were associated with capillary loss. The change was less pronounced in arterioles. However, in 3×Tg mice with cerebral microinfarcts, increasing arteriolar diameter and their wall cells were related with the strong oxidative DNA damage 8-hydroxy-2'-deoxyguanosine (8-OHdG), apoptosis (cleaved caspase 3), and sustained hypoxia (increased HIF-1α and VEGF/PKCε/extracellular signal regulated kinase or ERK pathway). Microocclusion enhanced the loss of the synaptic marker spinophilin, astrocytic number, and astrocyte-vascular coupling areas and demyelination of axons. DCPLA-ME prevented spatial memory defect; strong oxidative stress-related apoptosis; sustained hypoxia (by reducing HIF-1α and VEGF); and exaggerated cell repair in arteriolar walls, pericapillary space dilation, neuro-glial-vascular disruption, and demyelination. In conclusion, in 3×Tg mice with cerebral microinfarcts, sustained hypoxia (increased HIF-1α and VEGF signals) is dominant with arteriolar wall thickening, and DCPLA has a protective effect on sustained hypoxia.

Clinical Manifestations.

The accumulation of toxic amyloid-ß protein in brain is a hallmark of Alzheimer's disease. The accumulation of such toxicants is prevented by a cellular protein quality control system. Molecular chaperons, which further prevent proteins from misfolding and aggregating, are produced by this system, which is mostly activated in response to acute thermal stress. This study aims to determine the therapeutic effect of frequent thermal shock on the development of Alzheimer's disease METHOD: The induction of Alzheimer's disease was caused by the intracerebroventricular (ICV) injection of the Aß (1-42) peptide into the ventricular system of the mouse brain. The animals were divided into four groups: normal control (NC), disease control (DC), sham control (SC), water immersion/no heat group (NH), and hot water immersion/high heat group (HH). The ICV-Aß injection was given to the DC, NH, and HH groups to induce dementia and AD-like symptoms. The animals in the HH treatment group were given heat shock in the form of hot water immersion for a period of 4 weeks, where each session lasted for 20 minutes. The animals in the NH group were also exposed to water immersion for 20 minutes daily for a period of 4 weeks, but the water temperature was maintained at room temperature. After the completion of the treatment period, the behavioural and biochemical parameters of the animals were assessed for learning and memory defects. The enzyme-linked immunosorbent assay (ELISA) was carried out for the Aß estimation. Behavioural assessments in the Y-maze and morris water maze showed that the animals given daily heat exposure for a period of 4 weeks resisted the detrimental memory effects of the ICV-Aß injection and had better memory than the water immersion group with no heat treatment given. Increased levels of lipid peroxidation and decreased levels of glutathione were significantly (p<0.05) antagonised by hot water immersion treatment. ELISA showed the lower level of Aß in hot water immersion/high heat group animals when compared to the disease control animals. The study concluded that frequent heat exposure from hot baths and saunas may reduce the risk of developing dementia and Alzheimer's-like symptoms in old age.

Histone methylation mediated by NSD1 is required for the establishment and maintenance of neuronal identities

Appropriate histone modifications emerge as essential cell fate regulators of neuronal identities across neocortical areas and layers. Here we showed that NSD1, the methyltransferase for di-methylated lysine 36 of histone H3 (H3K36me2), controls both area and layer identities of the neocortex. Nsd1-ablated neocortex showed an area shift of all four primary functional regions and aberrant wiring of cortico-thalamic-cortical projections. Nsd1 conditional knockout mice displayed defects in spatial memory, motor learning, and coordination, resembling patients with the Sotos syndrome carrying NSD1 mutations. On Nsd1 loss, superficial-layer pyramidal neurons (PNs) progressively mis-expressed markers for deep-layer PNs, and PNs remained immature both morphologically and electrophysiologically. Loss of Nsd1 in postmitotic PNs causes genome-wide loss of H3K36me2 and re-distribution of DNA methylation, which accounts for diminished expression of neocortical layer specifiers but ectopic expression of non-neural genes. Together, H3K36me2 mediated by NSD1 is required for the establishment and maintenance of region- and layer-specific neocortical identities.

Mice deficient in complement C3 are protected against recognition memory deficits and astrogliosis induced by status epilepticus.

Status epilepticus (SE) can significantly increase the risk of temporal lobe epilepsy (TLE) and cognitive comorbidities. A potential candidate mechanism underlying memory defects in epilepsy may be the immune complement system. The complement cascade, part of the innate immune system, modulates inflammatory and phagocytosis signaling, and has been shown to contribute to learning and memory dysfunctions in neurodegenerative disorders. We previously reported that complement C3 is elevated in brain biopsies from human drug-resistant epilepsy and in experimental rodent models. We also found that SE-induced increases in hippocampal C3 levels paralleled the development of hippocampal-dependent spatial learning and memory deficits in rats. Thus, we hypothesized that SE-induced C3 activation contributes to this pathophysiology in a mouse model of SE and acquired TLE. In this study C3 knockout (KO) and wild type (WT) mice were subjected to one hour of pilocarpine-induced SE or sham conditions (control; C). Following a latent period of two weeks, recognition memory was assessed utilizing the novel object recognition (NOR) test. Western blotting was utilized to determine the protein levels of C3 in hippocampal lysates. In addition, we assessed the protein levels and distribution of the astrocyte marker glial fibrillary acidic protein (GFAP). In the NOR test, control WT + C or C3 KO + C mice spent significantly more time exploring the novel object compared to the familiar object. In contrast, WT+SE mice did not show preference for either object, indicating a memory defect. This deficit was prevented in C3 KO + SE mice, which performed similarly to controls. In addition, we found that SE triggered significant increases in the protein levels of GFAP in hippocampi of WT mice but not in C3 KO mice. These findings suggest that ablation of C3 prevents SE-induced recognition memory deficits and that a C3-astrocyte interplay may play a role. Therefore, it is possible that enhanced C3 signaling contributes to SE-associated cognitive decline during epileptogenesis and may serve as a potential therapeutic target for treating cognitive comorbidities in acquired TLE.

Blockade of adenosine A2A receptors reverses early spatial memory defects in the APP/PS1 mouse model of Alzheimer’s disease by promoting synaptic plasticity of adult-born granule cells

BackgroundThe over-activation of adenosine A2A receptors (A2AR) is closely implicated in cognitive impairments of Alzheimer's disease (AD). Growing evidence shows that A2AR blockade possesses neuroprotective effects on AD. Spatial navigation impairment is an early manifestation of cognitive deficits in AD. However, whether A2AR blockade can prevent early impairments in spatial cognitive function and the underlying mechanism is still unclear.MethodsA transgenic APP/PS1 mouse model of AD amyloidosis was used in this study. Behavioral tests were conducted to observe the protective effects of A2AR blockade on early spatial memory deficits in 4-month old APP/PS1 mice. To investigate the underlying synaptic mechanism of the protective effects of A2AR blockade, we further examined long-term potentiation (LTP) and network excitation/inhibition balance of dentate gyrus (DG) region, which is relevant to unique synaptic functions of immature adult-born granule cells (abGCs). Subsequently, the protective effects of A2AR blockade on dendritic morphology and synaptic plasticity of 6-week-old abGCs was investigated using retrovirus infection and electrophysiological recordings. The molecular mechanisms underlying neuroprotective properties of A2AR blockade on the synaptic plasticity of abGCs were further explored using molecular biology methods.ResultsAPP/PS1 mice displayed DG-dependent spatial memory deficits at an early stage. Additionally, impaired LTP and an imbalance in network excitation/inhibition were observed in the DG region of APP/PS1 mice, indicating synaptic structural and functional abnormalities of abGCs. A2AR was found to be upregulated in the hippocampus of the APP/PS1 mouse model of AD. Treatment with the selective A2AR antagonist SCH58261 for three weeks significantly ameliorated spatial memory deficits in APP/PS1 mice and markedly restored LTP and network excitation/inhibition balance in the DG region. Moreover, SCH58261 treatment restored dendritic morphology complexity and enhanced synaptic plasticity of abGCs in APP/PS1 mice. Furthermore, SCH58261 treatment alleviated the impairment of synaptic plasticity in abGCs. It achieved this by remodeling the subunit composition of NMDA receptors and increasing the proportion of NR2B receptors in abGCs of APP/PS1 mice.ConclusionsBlockade of A2AR improves early spatial memory deficits in APP/PS1 mice, possibly by reversing synaptic defects of abGCs. This finding suggests that A2AR blockade could be a potential therapy for AD.

Multidimensional autophagy nano-regulator boosts Alzheimer's disease treatment by improving both extra/intraneuronal homeostasis

Intraneuronal dysproteostasis and extraneuronal microenvironmental abnormalities in Alzheimer's disease (AD) collectively culminate in neuronal deterioration. In the context of AD, autophagy dysfunction, a multi-link obstacle involving autophagy downregulation and lysosome defects in neurons/microglia is highly implicated in intra/extraneuronal pathological processes. Therefore, multidimensional autophagy regulation strategies co-manipulating “autophagy induction” and “lysosome degradation” in dual targets (neuron and microglia) are more reliable for AD treatment. Accordingly, we designed an RP-1 peptide-modified reactive oxygen species (ROS)-responsive micelles (RT-NM) loading rapamycin or gypenoside XVII. Guided by RP-1 peptide, the ligand of receptor for advanced glycation end products (RAGE), RT-NM efficiently targeted neurons and microglia in AD-affected region. This nano-combination therapy activated the whole autophagy-lysosome pathway by autophagy induction (rapamycin) and lysosome improvement (gypenoside XVII), thus enhancing autophagic degradation of neurotoxic aggregates and inflammasomes, and promoting Aβ phagocytosis. Resultantly, it decreased aberrant protein burden, alleviated neuroinflammation, and eventually ameliorated memory defects in 3 × Tg-AD transgenic mice. Our research developed a multidimensional autophagy nano-regulator to boost the efficacy of autophagy-centered AD therapy.

N6-Methyladenosine mRNA Modification: From Modification Site Selectivity to Neurological Functions.

The development of various chemical methods has enabled scientists to decipher the distribution features and biological functions of RNA modifications in the past decade. In addition to modifying noncoding RNAs such as tRNAs and rRNAs, N6-methyladenosine (m6A) has been proven to be the most abundant internal chemical modification on mRNAs in eukaryotic cells and is also the most widely studied mRNA modification to date. Extensive studies have repeatedly demonstrated the important functions of m6A in various biological conditions, ranging from embryonic organ development to adult organ function and pathogenesis. Unlike DNA methylation which is relatively stable, the reversible m6A modification on mRNA is highly dynamic and easily influenced by various internal or external factors, such as cell type, developmental stage, nutrient supply, circadian rhythm, and environmental stresses.In this Account, we review our previous findings on the site selectivity mechanisms regulating m6A formation, as well as the physiological roles of m6A modification in cerebellum development and long-term memory consolidation. In our initial efforts to profile m6A in various types of mouse and human cells, we surprisingly found that the sequence motifs surrounding m6A sites were often complementary with the seed sequences of miRNAs. By manipulating the abundance of the miRNA biogenesis enzyme Dicer or individual miRNAs or mutating miRNA sequences, we were able to reveal a new role of nucleus localized miRNAs, which is to guide the m6A methyltransferase METTL3 to bind to mRNAs and to promote m6A formation. As a result, we partially answered the question of why only a small proportion of m6A motifs within an mRNA could have m6A modification at a certain time point. We further explored the functions of m6A modification in regulating brain development and brain functions. We found that cerebellum had the most severe defects when Mettl3 was knocked out in developing mouse embryonic brain and revealed that the underlying mechanisms could be attributed to aberrant mRNA splicing and enhanced cell apoptosis under m6A deficit conditions. On the other hand, knocking out Mettl3 in postnatal hippocampus did not cause morphological defects in the mouse brain but impaired the efficacy of long-term memory consolidation. Under learning stimuli, formation of m6A modifications could be detected on transcripts encoding proteins related to dendrite growth, synapse formation, and other memory related functions. Loss of m6A modifications on these transcripts would result in translation deficiency and reduced protein production, particularly in the translation of early response genes, and therefore would compromise the efficacy of long-term memory consolidation. Interestingly, excessive training sessions or increased training intensity could overcome such m6A deficiency related memory defects, which is likely due to the longer turnover cycle and the cumulative abundance of proteins throughout the training process. In addition to revealing the roles of m6A modification in regulating long-term memory formation, our work also demonstrated an effective method for studying memory formation efficacy. As the lack of an appropriate model for studying memory formation efficacy has been a long-lasting problem in the field of neural science, our hippocampus-specific postnatal m6A knockout model could also be utilized to study other questions related to memory formation efficacy.

KDM2B regulates hippocampal morphogenesis by transcriptionally silencing Wnt signaling in neural progenitors

The hippocampus plays major roles in learning and memory, and its formation requires precise coordination of patterning, cell proliferation, differentiation, and migration. Here we removed the chromatin-association capability of KDM2B in the progenitors of developing dorsal telencephalon (Kdm2b∆CxxC) to discover that Kdm2b∆CxxC hippocampus, particularly the dentate gyrus, became drastically smaller with disorganized cellular components and structure. Kdm2b∆CxxC mice display prominent defects in spatial memory, motor learning and fear conditioning, resembling patients with KDM2B mutations. The migration and differentiation of neural progenitor cells is greatly impeded in the developing Kdm2b∆CxxC hippocampus. Mechanism studies reveal that Wnt signaling genes in developing Kdm2b∆CxxC hippocampi are de-repressed due to reduced enrichment of repressive histone marks by polycomb repressive complexes. Activating the Wnt signaling disturbs hippocampal neurogenesis, recapitulating the effect of KDM2B loss. Together, we unveil a previously unappreciated gene repressive program mediated by KDM2B that controls progressive fate specifications and cell migration, hence morphogenesis of the hippocampus.

Inborn errors of immunity underlying defective T-cell memory.

T-cell memory is a complex process not well understood involving specific steps, pathways and different T-cell subpopulations. Inborn errors of immunity (IEIs) represent unique models to decipher some of these requirements in humans. More than 500 different IEIs have been reported to date, and recently a subgroup of monogenic disorders characterized by memory T-cell defects has emerged, providing novel insights into the pathways of T-cell memory generation and maintenance, although this new knowledge is mostly restricted to peripheral blood T-cell memory populations. This review draws up an inventory of the main and recent IEIs associated with T-cell memory defects and their mice models, with a particular focus on the nuclear factor kappa B (NF-κB) signalling pathway, including the scaffold protein capping protein regulator and myosin 1 linker 2 (CARMIL2) and the T-cell co-stimulatory molecules CD28 and OX-40. Besides NF-κB, IKZF1 (IKAROS), a key transcription factor of haematopoiesis and STAT3-dependent interleukin-6 signals involving the transcription factor ZNF341 also appear to be important for the generation of T cell memory. Somatic reversion mosaicism in memory T cells is documented for several gene defects supporting the critical role of these factors in the development of memory T cells with a potential clinical benefit. Systematic examination of T-cell memory subsets could be helpful in the diagnosis of IEIs.

Coding and bounds for partially defective memory cells

This paper considers coding for so-called partially stuck (defect) memory cells. Such memory cells can only store partial information as some of their levels cannot be used fully due to, e.g., wearout. First, we present new constructions that are able to mask u partially stuck cells while correcting at the same time t random errors. The process of “masking” determines a word whose entries coincide with writable levels at the (partially) stuck cells. For u>1 and alphabet size q>2, our new constructions improve upon the required redundancy of known constructions for t=0, and require less redundancy for masking partially stuck cells than former works required for masking fully stuck cells (which cannot store any information). Second, we show that treating some of the partially stuck cells as erroneous cells can decrease the required redundancy for some parameters. Lastly, we derive Singleton-like, sphere-packing-like, and Gilbert–Varshamov-like bounds. Numerical comparisons state that our constructions match the Gilbert–Varshamov-like bounds for several code parameters, e.g., BCH codes that contain all-one word by our first construction.