Microglial and Astrocytic Responses in the Human Midcingulate Cortex in Huntington's Disease.

OBJECTIVE: Patients with Huntington's disease can present with variable difficulties of motor functioning, mood, and cognition. Neurodegeneration occurs in the anterior cingulate cortex of some patients with Huntington's disease and is linked to the presentation of mood symptomatology. Neuroinflammation, perpetrated by activated microglia and astrocytes, has been reported in Huntington's disease and may contribute to disease progression and presentation. This study sought to quantify the density of mutant huntingtin protein and neuroinflammatory glial changes in the midcingulate cortex of postmortem patients with Huntington's disease and determine if either correlates with the presentation of mood, motor, or mixed symptomatology. METHODS: Free-floating immunohistochemistry quantified 1C2 immunolabeling density as an indicative marker of mutant huntingtin protein, and protein and morphological markers of astrocyte (EAAT2, Cx43, and GFAP), and microglial (Iba1 and HLA-DP/DQ/DR) activation. Relationships among the level of microglial activation, mutant huntingtin burden, and case characteristics were explored using correlative analysis. RESULTS: We report alterations in activated microglia number and morphology in the midcingulate cortex of Huntington's disease cases with predominant mood symptomatology. An increased proportion of activated microglia was observed in the midcingulate of all Huntington's disease cases and positively correlated with 1C2 burden. Alterations in the astrocytic glutamate transporter EAAT2 were observed in the midcingulate cortex of patients associated with mood symptoms. INTERPRETATION: This study presents pathological changes in microglia and astrocytes in the midcingulate cortex in Huntington's disease, which coincide with mood symptom presentation. These findings further the understanding of neuroinflammation in Huntington's disease, a necessary step for developing inflammation-targeted therapeutics. ANN NEUROL 2023;94:895-910.

Is Hormone Replacement Therapy a Risk Factor or a Therapeutic Option for Alzheimer's Disease?

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that accounts for more than half of all dementia cases in the elderly. Interestingly, the clinical manifestations of AD disproportionately affect women, comprising two thirds of all AD cases. Although the underlying mechanisms for these sex differences are not fully elucidated, evidence suggests a link between menopause and a higher risk of developing AD, highlighting the critical role of decreased estrogen levels in AD pathogenesis. The focus of this review is to evaluate clinical and observational studies in women, which have investigated the impact of estrogens on cognition or attempted to answer the prevailing question regarding the use of hormone replacement therapy (HRT) as a preventive or therapeutic option for AD. The articles were retrieved through a systematic review of the databases: OVID, SCOPUS, and PubMed (keywords "memory", "dementia," "cognition," "Alzheimer's disease", "estrogen", "estradiol", "hormone therapy" and "hormone replacement therapy" and by searching reference sections from identified studies and review articles). This review presents the relevant literature available on the topic and discusses the mechanisms, effects, and hypotheses that contribute to the conflicting findings of HRT in the prevention and treatment of age-related cognitive deficits and AD. The literature suggests that estrogens have a clear role in modulating dementia risk, with reliable evidence showing that HRT can have both a beneficial and a deleterious effect. Importantly, recommendation for the use of HRT should consider the age of initiation and baseline characteristics, such as genotype and cardiovascular health, as well as the dosage, formulation, and duration of treatment until the risk factors that modulate the effects of HRT can be more thoroughly investigated or progress in the development of alternative treatments can be made.

Tonabersat Significantly Reduces Disease Progression in an Experimental Mouse Model of Multiple Sclerosis.

Multiple sclerosis (MS) is a neurodegenerative disease marked by chronic neuroinflammation thought to be mediated by the inflammasome pathway. Connexin 43 (Cx43) hemichannels contribute to the activation of the inflammasome through the release of adenosine triphosphate (ATP) inflammasome activation signals. The objective of the study was to evaluate if the Cx43 hemichannel blocker, tonabersat, is effective in modulating the inflammatory response and reducing disability in the myelin oligodendrocyte glycoprotein 35-55-induced experimental autoimmune encephalomyelitis (MOG35-55 EAE) model of MS. Here, we show that the Cx43 hemichannel blocking drug, tonabersat, significantly reduced expression of neuroinflammatory markers for microglial activation (ionized calcium-binding adapter molecule 1 (Iba1)) and astrogliosis (glial fibrillary acidic protein (GFAP)) while preserving myelin basic protein (MBP) expression levels in the corpus callosum, motor cortex, and striatum regions of the brain in MOG35-55 EAE mice. Reduced NOD-like receptor protein 3 (NLRP3) inflammasome complex assembly and Caspase-1 activation confirmed the drug's mode of action. MOG35-55 EAE mice showed clinical signs of MS, but MOG35-55 EAE mice treated with tonabersat retained behavior closer to normal. These data suggest that clinical trial phase IIb-ready tonabersat may merit further investigation as a promising candidate for MS treatment.

Cation-Chloride Cotransporters KCC2 and NKCC1 as Therapeutic Targets in Neurological and Neuropsychiatric Disorders.

Neurological diseases including Alzheimer's, Huntington's disease, Parkinson's disease, Down syndrome and epilepsy, and neuropsychiatric disorders such as schizophrenia, are conditions that affect not only individuals but societies on a global scale. Current therapies offer a means for small symptomatic relief, but recently there has been increasing demand for therapeutic alternatives. The γ-aminobutyric acid (GABA)ergic signaling system has been investigated for developing new therapies as it has been noted that any dysfunction or changes to this system can contribute to disease progression. Expression of the K-Cl-2 (KCC2) and N-K-C1-1 (NKCC1) cation-chloride cotransporters (CCCs) has recently been linked to the disruption of GABAergic activity by affecting the polarity of GABAA receptor signaling. KCC2 and NKCC1 play a part in multiple neurological and neuropsychiatric disorders, making them a target of interest for potential therapies. This review explores current research suggesting the pathophysiological role and therapeutic importance of KCC2 and NKCC1 in neuropsychiatric and neurological disorders.

Neuroprotective Effect of Caffeine in Alzheimer's Disease.

Alzheimer's disease (AD) is the leading cause of dementia, predicted to be the most significant health burden of the 21st century, with an estimated 131.5 million dementia patients by the year 2050. This review aims to provide an overview of the effect of caffeine on AD and cognition by summarizing relevant research conducted on this topic. We searched the Web of Science core collection and PubMed for studies related to the effect of caffeine on AD and cognition using title search terms: caffeine; coffee; Alzheimer's; cognition. There is suggestive evidence from clinical studies that caffeine is neuroprotective against dementia and possibly AD (20 out of 30 studies support this), but further studies, such as the "ideal" study proposed in this review, are required to prove this link. Clinical studies also indicate that caffeine is a cognitive normalizer and not a cognitive enhancer. Furthermore, clinical studies suggest the neuroprotective effect of caffeine might be confounded by gender. There is robust evidence based on in vivo and in vitro studies that caffeine has neuroprotective properties in AD animal models (21 out of 22 studies support this), but further studies are needed to identify the mechanistic pathways mediating these effects.

Beta-Amyloid (Aß1-42) Increases the Expression of NKCC1 in the Mouse Hippocampus.

Alzheimer's disease (AD) is a neurodegenerative disorder with an increasing need for developing disease-modifying treatments as current therapies only provide marginal symptomatic relief. Recent evidence suggests the γ-aminobutyric acid (GABA) neurotransmitter system undergoes remodeling in AD, disrupting the excitatory/inhibitory (E/I) balance in the brain. Altered expression levels of K-Cl-2 (KCC2) and N-K-Cl-1 (NKCC1), which are cation-chloride cotransporters (CCCs), have been implicated in disrupting GABAergic activity by regulating GABAA receptor signaling polarity in several neurological disorders, but these have not yet been explored in AD. NKCC1 and KCC2 regulate intracellular chloride [Cl-]i by accumulating and extruding Cl-, respectively. Increased NKCC1 expression in mature neurons has been reported in these disease conditions, and bumetanide, an NKCC1 inhibitor, is suggested to show potential therapeutic benefits. This study used primary mouse hippocampal neurons to explore if KCC2 and NKCC1 expression levels are altered following beta-amyloid (Aß1-42) treatment and the potential neuroprotective effects of bumetanide. KCC2 and NKCC1 expression levels were also examined in 18-months-old male C57BL/6 mice following bilateral hippocampal Aß1-42 stereotaxic injection. No change in KCC2 and NKCC1 expression levels were observed in mouse hippocampal neurons treated with 1 nM Aß1-42, but NKCC1 expression increased 30-days post-Aß1-42-injection in the CA1 region of the mouse hippocampus. Primary mouse hippocampal cultures were treated with 1 nM Aß1-42 alone or with various concentrations of bumetanide (1 µM, 10 µM, 100 µM, 1 mM) to investigate the effect of the drug on cell viability. Aß1-42 produced 53.1 ± 1.4% cell death after 5 days, and the addition of bumetanide did not reduce this. However, the drug at all concentrations significantly reduced cell viability, suggesting bumetanide is highly neurotoxic. In summary, these results suggest that chronic exposure to Aß1-42 alters the balance of KCC2 and NKCC1 expression in a region-and layer-specific manner in mouse hippocampal tissue; therefore, this process most likely contributes to altered hippocampal E/I balance in this model. Furthermore, bumetanide induces hippocampal neurotoxicity, thus questioning its suitability for AD therapy. Further investigations are required to examine the effects of Aß1-42 on KCC2 and NKCC1 expression and whether targeting CCCs might offer a therapeutic approach for AD.

Amyloid-beta1-42 induced glutamatergic receptor and transporter expression changes in the mouse hippocampus.

Alzheimer's disease (AD) is the leading type of dementia worldwide. With an increasing burden of an aging population coupled with the lack of any foreseeable cure, AD warrants the current intense research effort on the toxic effects of an increased concentration of beta-amyloid (Aß) in the brain. Glutamate is the main excitatory brain neurotransmitter and it plays an essential role in the function and health of neurons and neuronal excitability. While previous studies have shown alterations in expression of glutamatergic signaling components in AD, the underlying mechanisms of these changes are not well understood. This is the first comprehensive anatomical study to characterize the subregion- and cell layer-specific long-term effect of Aß1-42 on the expression of specific glutamate receptors and transporters in the mouse hippocampus, using immunohistochemistry with confocal microscopy. Outcomes are examined 30 days after Aß1-42 stereotactic injection in aged male C57BL/6 mice. We report significant decreases in density of the glutamate receptor subunit GluA1 and the vesicular glutamate transporter (VGluT) 1 in the conus ammonis 1 region of the hippocampus in the Aß1-42 injected mice compared with artificial cerebrospinal fluid injected and naïve controls, notably in the stratum oriens and stratum radiatum. GluA1 subunit density also decreased within the dentate gyrus dorsal stratum moleculare in Aß1-42 injected mice compared with artificial cerebrospinal fluid injected controls. These changes are consistent with findings previously reported in the human AD hippocampus. By contrast, glutamate receptor subunits GluA2, GluN1, GluN2A, and VGluT2 showed no changes in expression. These findings indicate that Aß1-42 induces brain region and layer specific expression changes of the glutamatergic receptors and transporters, suggesting complex and spatial vulnerability of this pathway during development of AD neuropathology. Read the Editorial Highlight for this article on page 7. Cover Image for this issue: https://doi.org/10.1111/jnc.14763.

Impaired Expression of GABA Signaling Components in the Alzheimer's Disease Middle Temporal Gyrus.

γ-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter, playing a central role in the regulation of cortical excitability and the maintenance of the excitatory/inhibitory (E/I) balance. Several lines of evidence point to a remodeling of the cerebral GABAergic system in Alzheimer's disease (AD), with past studies demonstrating alterations in GABA receptor and transporter expression, GABA synthesizing enzyme activity and focal GABA concentrations in post-mortem tissue. AD is a chronic neurodegenerative disorder with a poorly understood etiology and the temporal cortex is one of the earliest regions in the brain to be affected by AD neurodegeneration. Utilizing NanoString nCounter analysis, we demonstrate here the transcriptional downregulation of several GABA signaling components in the post-mortem human middle temporal gyrus (MTG) in AD, including the GABAA receptor α1, α2, α3, α5, ß1, ß2, ß3, δ, γ2, γ3, and θ subunits and the GABAB receptor 2 (GABABR2) subunit. In addition to this, we note the transcriptional upregulation of the betaine-GABA transporter (BGT1) and GABA transporter 2 (GAT2), and the downregulation of the 67 kDa isoform of glutamate decarboxylase (GAD67), the primary GABA synthesizing enzyme. The functional consequences of these changes require further investigation, but such alterations may underlie disruptions to the E/I balance that are believed to contribute to cognitive decline in AD.

An 5 GABAA Receptor Inverse Agonist, 5IA, Attenuates Amyloid Beta-Induced Neuronal Death in Mouse Hippocampal Cultures.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which no cognition-restoring therapies exist. Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain. Increasing evidence suggests a remodeling of the GABAergic system in AD, which might represent an important therapeutic target. An inverse agonist of 5 subunit-containing GABAA receptors (α5GABAARs), 3-(5-Methylisoxazol-3-yl)-6-[(1-methyl-1,2,3-triazol-4-yl)methyloxy]-1,2,4-triazolo[3-a]phthalazine (5IA) has cognition-enhancing properties. This study aimed to characterize the effects of 5IA on amyloid beta (A1-42)-induced molecular and cellular changes. Mouse primary hippocampal cultures were exposed to either A1-42 alone, or 5IA alone, 5IA with A1-42 or vehicle alone, and changes in cell viability and mRNA expression of several GABAergic signaling components were assessed. Treatment with 100 nM of 5IA reduced A1-42-induced cell loss by 23.8% (p < 0.0001) after 6 h and by 17.3% after 5 days of treatment (p < 0.0001). Furthermore, we observed an A1-42-induced increase in ambient GABA levels, as well as upregulated mRNA expression of the GABAAR α2,α5,2/3 subunits and the GABABR R1 and R2 subunits. Such changes in GABARs expression could potentially disrupt inhibitory neurotransmission and normal network activity. Treatment with 5IA restored A1-42-induced changes in the expression of α5GABAARs. In summary, this compound might hold neuroprotective potential and represent a new therapeutic avenue for AD.

Amyloid-Beta1-42 -Induced Increase in GABAergic Tonic Conductance in Mouse Hippocampal CA1 Pyramidal Cells.

Alzheimer's disease (AD) is a complex and chronic neurodegenerative disorder that involves a progressive and severe decline in cognition and memory. During the last few decades a considerable amount of research has been done in order to better understand tau-pathology, inflammatory activity and neuronal synapse loss in AD, all of them contributing to cognitive decline. Early hippocampal network dysfunction is one of the main factors associated with cognitive decline in AD. Much has been published about amyloid-beta1-42 (Aß1-42)-mediated excitotoxicity in AD. However, increasing evidence demonstrates that the remodeling of the inhibitory gamma-aminobutyric acid (GABAergic) system contributes to the excitatory/inhibitory (E/I) disruption in the AD hippocampus, but the underlying mechanisms are not well understood. In the present study, we show that hippocampal injection of Aß1-42 is sufficient to induce cognitive deficits 7 days post-injection. We demonstrate using in vitro whole-cell patch-clamping an increased inhibitory GABAergic tonic conductance mediated by extrasynaptic type A GABA receptors (GABAARs), recorded in the CA1 region of the mouse hippocampus following Aß1-42 micro injection. Such alterations in GABA neurotransmission and/or inhibitory GABAARs could have a significant impact on both hippocampal structure and function, causing E/I balance disruption and potentially contributing to cognitive deficits in AD.

GABAA receptor subunit expression changes in the human Alzheimer's disease hippocampus, subiculum, entorhinal cortex and superior temporal gyrus.

Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. GABA type A receptors (GABAA Rs) are severely affected in Alzheimer's disease (AD). However, the distribution and subunit composition of GABAA Rs in the AD brain are not well understood. This is the first comprehensive study to show brain region- and cell layer-specific alterations in the expression of the GABAA R subunits α1-3, α5, ß1-3 and γ2 in the human AD hippocampus, entorhinal cortex and superior temporal gyrus. In late-stage AD tissue samples using immunohistochemistry we found significant alteration of all investigated GABAA Rs subunits except for α3 and ß1 that were well preserved. The most prominent changes include an increase in GABAA R α1 expression associated with AD in all layers of the CA3 region, in the stratum (str.) granulare and hilus of the dentate gyrus. We found a significant increase in GABAA R α2 expression in the str. oriens of the CA1-3, str. radiatum of the CA2,3 and decrease in the str. pyramidale of the CA1 region in AD cases. In AD there was a significant increase in GABAA R α5 subunit expression in str. pyramidale, str. oriens of the CA1 region and decrease in the superior temporal gyrus. We also found a significant decrease in the GABAA R ß3 subunit immunoreactivity in the str. oriens of the CA2, str. granulare and str. moleculare of the dentate gyrus. In conclusion, these findings indicate that the expression of the GABAA R subunits shows brain region- and layer-specific alterations in AD, and these changes could significantly influence and alter GABAA R function in the disease. Cover Image for this issue: doi: 10.1111/jnc.14179.

The GABAergic system as a therapeutic target for Alzheimer's disease.

Glutamatergic and cholinergic dysfunction are well-attested features of Alzheimer's disease (AD), progressing with other pathological indices of the disorder and exacerbating neuronal and network dysfunction. However, relatively little attention has been paid to the inhibitory component of the excitatory/inhibitory (E/I) network, particularly dysfunction in the gamma-aminobutyric acid (GABA) signaling system. There is growing evidence in support of GABAergic remodeling in the AD brain, potentially beginning in early stages of disease pathogenesis, and this could thus be a valid molecular target for drug development and pharmacological therapies. Several GABAergic drugs have been tested for efficacy in attenuating or reversing various features and symptoms of AD, and this could represent a novel path by which we might address the growing need for more effective and benign therapies.

Towards a Better Understanding of GABAergic Remodeling in Alzheimer's Disease.

γ-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the vertebrate brain. In the past, there has been a major research drive focused on the dysfunction of the glutamatergic and cholinergic neurotransmitter systems in Alzheimer's disease (AD). However, there is now growing evidence in support of a GABAergic contribution to the pathogenesis of this neurodegenerative disease. Previous studies paint a complex, convoluted and often inconsistent picture of AD-associated GABAergic remodeling. Given the importance of the GABAergic system in neuronal function and homeostasis, in the maintenance of the excitatory/inhibitory balance, and in the processes of learning and memory, such changes in GABAergic function could be an important factor in both early and later stages of AD pathogenesis. Given the limited scope of currently available therapies in modifying the course of the disease, a better understanding of GABAergic remodeling in AD could open up innovative and novel therapeutic opportunities.

Effect of Estradiol on Neurotrophin Receptors in Basal Forebrain Cholinergic Neurons: Relevance for Alzheimer's Disease.

The basal forebrain is home to the largest population of cholinergic neurons in the brain. These neurons are involved in a number of cognitive functions including attention, learning and memory. Basal forebrain cholinergic neurons (BFCNs) are particularly vulnerable in a number of neurological diseases with the most notable being Alzheimer's disease, with evidence for a link between decreasing cholinergic markers and the degree of cognitive impairment. The neurotrophin growth factor system is present on these BFCNs and has been shown to promote survival and differentiation on these neurons. Clinical and animal model studies have demonstrated the neuroprotective effects of 17ß-estradiol (E2) on neurodegeneration in BFCNs. It is believed that E2 interacts with neurotrophin signaling on cholinergic neurons to mediate these beneficial effects. Evidence presented in our recent study confirms that altering the levels of circulating E2 levels via ovariectomy and E2 replacement significantly affects the expression of the neurotrophin receptors on BFCN. However, we also showed that E2 differentially regulates neurotrophin receptor expression on BFCNs with effects depending on neurotrophin receptor type and neuroanatomical location. In this review, we aim to survey the current literature to understand the influence of E2 on the neurotrophin system, and the receptors and signaling pathways it mediates on BFCN. In addition, we summarize the physiological and pathophysiological significance of E2 actions on the neurotrophin system in BFCN, especially focusing on changes related to Alzheimer's disease.

Non-classical effects of estradiol on cAMP responsive element binding protein phosphorylation in gonadotropin-releasing hormone neurons: mechanisms and role.

Gonadotropin-releasing hormone (GnRH) is produced by a heterogenous neuronal population in the hypothalamus to control pituitary gonadotropin production and reproductive function in all mammalian species. Estradiol is a critical component for the communication between the gonads and the central nervous system. Resolving the mechanisms by which estradiol modulates GnRH neurons is critical for the understanding of how fertility is regulated. Extensive studies during the past decades have provided compelling evidence that estradiol has the potential to alter the intracellular signal transduction mechanisms. The common target of many signaling pathways is the phosphorylation of a key transcription factor, the cAMP response element binding protein (CREB). This review first addresses the aspects of estradiol action on CREB phosphorylation (pCREB) in GnRH neurons. Secondly, this review considers the receptors and signaling network that regulates estradiol's action on pCREB within GnRH neurons and finally it summarizes the physiological significance of CREB to estrogen feedback.

Alzheimer's Disease-associated Region-specific Decrease of Vesicular Glutamate Transporter Immunoreactivity inthe Medial Temporal Lobe and Superior Temporal Gyrus.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there are very limited treatment options. Dysfunction of the excitatory neurotransmitter system is thought to play a major role in the pathogenesis of this condition. Vesicular glutamate transporters (VGLUTs) are key to controlling the quantal release of glutamate. Thus, expressional changes in disease can have implications for aberrant neuronal activity, raising the possibility of a therapeutic target. There is no information regarding the expression of VGLUTs in the human medial temporal lobe in AD, one of the earliest and most severely affected brain regions. This study aimed to quantify and compare the layer-specific expression of VGLUT1 and VGLUT2 between control and AD cases in the hippocampus, subiculum, entorhinal cortex, and superior temporal gyrus. Free-floating fluorescent immunohistochemistry was used to label VGLUT1 and VGLUT2 in the hippocampus, subiculum, entorhinal cortex, and superior temporal gyrus. Sections were imaged using laser-scanning confocal microscopy and transporter densitometric analysis was performed. VGLUT1 density was not significantly different in AD tissue, except lower staining density observed in the dentate gyrus stratum moleculare (p = 0.0051). VGLUT2 expression was not altered in the hippocampus and entorhinal cortex of AD cases but was significantly lower in the subiculum (p = 0.015) and superior temporal gyrus (p = 0.0023). This study indicates a regionally specific vulnerability of VGLUT1 and VGLUT2 expression in the medial temporal lobe and superior temporal gyrus in AD. However, the causes and functional consequences of these disturbances need to be further explored to assess VGLUT1 and VGLUT2 as viable therapeutic targets.

The role of cAMP response element-binding protein in estrogen negative feedback control of gonadotropin-releasing hormone neurons.

The mechanisms through which estradiol (E2) regulates gonadotropin-releasing hormone (GnRH) neurons to control fertility are unclear. Previous studies have demonstrated that E2 rapidly phosphorylates cAMP response element-binding protein (CREB) in GnRH neurons in vivo. In the present study, we used GnRH neuron-specific CREB-deleted mutant mice [GnRH-CREB knock-outs (KOs)] with and without global cAMP response element modulator (CREM) deletion (global-CREM KOs) to investigate the role of CREB in estrogen negative feedback on GnRH neurons. Evaluation of GnRH-CREB KO mice with and without global CREM deletion revealed normal puberty onset. Although estrus cycle length in adults was the same in controls and knock-out mice, cycles in mutant mice consisted of significantly longer periods of diestrus and less estrus. In GnRH-CREB KO mice, basal levels of luteinizing hormone (LH) and the postovariectomy increment in LH were normal, but the ability of E2 to rapidly suppress LH was significantly blunted. In contrast, basal and postovariectomy LH levels were abnormal in GnRH-CREB KO/global-CREM KO mice. Fecundity studies showed that GnRH-CREB KO with and without global CREM deletion were normal up to ∼9 months of age, at which time they became prematurely reproductively senescent. Morphological analysis of GnRH neurons revealed a significant reduction (p < 0.01) in GnRH somatic spine density of GnRH-CREB KO mice compared to control females. These observations implicate CREB within the GnRH neuron as an important target for E2's negative feedback actions. They also indicate that the rapid modulation of CREB by E2 is of physiological significance in the CNS.

Retinal inner nuclear layer thickness in the diagnosis of cognitive impairment explored using a C57BL/6J mouse model.

Major neurocognitive disorder (NCD) affects over 55 million people worldwide and is characterized by cognitive impairment (CI). This study aimed to develop a non-invasive diagnostic test for CI based upon retinal thickness measurements explored in a mouse model. Discrimination indices and retinal layer thickness of healthy C57BL/6J mice were quantified through a novel object recognition test (NORT) and ocular coherence tomography (OCT), respectively. Based on criteria from the Diagnostic and statistical manual of mental disorders 5th ed. (DSM-V), a diagnostic test was generated by transforming data into rolling monthly averages and categorizing mice into those with and without CI and those with a high or low decline in retinal layer thickness. Only inner nuclear layer thickness had a statistically significant relationship with discrimination indices. Furthermore, our diagnostic test was 85.71% sensitive and 100% specific for diagnosing CI, with a positive predictive value of 100%. These findings have potential clinical implications for the early diagnosis of CI in NCD. However, further investigation in comorbid mice and humans is warranted.

The central role of the NLRP3 inflammasome pathway in the pathogenesis of age-related diseases in the eye and the brain.

With increasing age, structural changes occur in the eye and brain. Neuronal death, inflammation, vascular disruption, and microglial activation are among many of the pathological changes that can occur during ageing. Furthermore, ageing individuals are at increased risk of developing neurodegenerative diseases in these organs, including Alzheimer's disease (AD), Parkinson's disease (PD), glaucoma and age-related macular degeneration (AMD). Although these diseases pose a significant global public health burden, current treatment options focus on slowing disease progression and symptomatic control rather than targeting underlying causes. Interestingly, recent investigations have proposed an analogous aetiology between age-related diseases in the eye and brain, where a process of chronic low-grade inflammation is implicated. Studies have suggested that patients with AD or PD are also associated with an increased risk of AMD, glaucoma, and cataracts. Moreover, pathognomonic amyloid-ß and α-synuclein aggregates, which accumulate in AD and PD, respectively, can be found in ocular parenchyma. In terms of a common molecular pathway that underpins these diseases, the nucleotide-binding domain, leucine-rich-containing family, and pyrin domain-containing-3 (NLRP3) inflammasome is thought to play a vital role in the manifestation of all these diseases. This review summarises the current evidence regarding cellular and molecular changes in the brain and eye with age, similarities between ocular and cerebral age-related diseases, and the role of the NLRP3 inflammasome as a critical mediator of disease propagation in the eye and the brain during ageing.

EAAT2 as a therapeutic research target in Alzheimer's disease: A systematic review.

Glutamate is the main excitatory neurotransmitter in the human central nervous system, responsible for a wide variety of normal physiological processes. Glutamatergic metabolism and its sequestration are tightly regulated in the normal human brain, and it has been demonstrated that dysregulation of the glutamatergic system can have wide-ranging effects both in acute brain injury and neurodegenerative diseases. The excitatory amino acid transporter 2 (EAAT2) is the dominant glutamatergic transporter in the human brain, responsible for efficient removal of glutamate from the synaptic cleft for recycling within glial cells. As such, it has a key role in maintaining excitatory-inhibitory homeostasis. Animal studies have demonstrated dysregulation or alterations of EAAT2 expression can have implications in neurodegenerative disorders. Despite extensive research into glutamatergic alterations in AD mouse models, there is a lack of studies examining the expression of EAAT2 within the AD human brain. In this systematic review, 29 articles were identified that either analyzed EAAT2 expression in the AD human brain or used a human-derived cell culture. Studies were inconclusive as to whether EAAT2 was upregulated or downregulated in AD. However, changes in localization and correlation between EAAT2 expression and symptomatology was noted. These findings implicate EAAT2 alterations as a key process in AD progression and highlight the need for further research into the characterization of EAAT2 processes in normal physiology and disease in human tissue and to identify compounds that can act as EAAT2 neuromodulators.