GPR75 is an orphan G protein-coupled receptor for which there is currently limited information and its function in physiology and disease is only recently beginning to emerge. This orphan receptor is expressed in the retina but its function in the eye is unknown. The earliest studies on GPR75 were conducted in the retina, where the receptor was first identified and cloned and mutations in the receptor were identified as a possible contributor to retinal degenerative disease. Despite these sporadic reports, the function of GPR75 in the retina and in retinal disease has yet to be explored. To assess whether GPR75 has a functional role in the retina, the retina of Gpr75 knockout mice was characterized. Knockout mice displayed a mild progressive retinal degeneration, which was accompanied by oxidative stress. The degeneration was because of the loss of both M-cone and S-cone photoreceptor cells. Housing mice under constant dark conditions reduced oxidative stress but did not prevent cone photoreceptor cell loss, indicating that oxidative stress is not a primary cause of the observed retinal degeneration. Studies here demonstrate an important role for GPR75 in maintaining the health of cone photoreceptor cells and that Gpr75 knockout mice can be used as a model to study cone photoreceptor cell loss.

This is a review of a recently published book entitled 'Alzheimer's Disease Research: What has guided research so far and why it is high time for a paradigm shift' by Christian Behl, a leading contributor to the field of Alzheimer disease over the last three decades. It presents a personal viewpoint on the historical developments in dementia research and therapeutics from its early beginnings through to the current day. The conflicting hypotheses, the therapeutic trials, the successes and the failures of the vast research infrastructure devoted to dissecting the aberrant pathways underlying the inexorable progression of this ultimately fatal neurodegenerative disease are discussed. It is based, among others, on numerous personal discussions of the author with other leading researchers in the field, and thus gives this (hi)story of Alzheimer research a personal touch and spotlight on controversies that distinguishes it from other books in the field.

The relationship between liver dysfunction and dementia has been researched extensively but remains poorly understood. In this study, we investigate the longitudinal and cross-sectional associations between liver function and liver diseases and risk of incident dementia, impaired cognition, and brain structure abnormalities using Cox proportion hazard model and linear regression model. 431 699 participants with a mean of 8.65 (standard deviation [SD] 2.61) years of follow-up were included from the UK Biobank; 5542 all-cause dementia (ACD), 2427 Alzheimer's disease (AD), and 1282 vascular dementia (VaD) cases were documented. We observed that per SD decreases in alanine transaminase (ALT; hazard ratio [HR], 0.917; PFDR  <0.001) and per SD increases in aspartate aminotransferase (AST; HR, 1.048; PFDR  = 0.010), AST to ALT ratio (HR, 1.195; PFDR  <0.001), gamma-glutamyl transpeptidase (GGT; HR, 1.066; PFDR  <0.001), alcoholic liver disease (ALD; HR, 2.872; PFDR  <0.001), and fibrosis and cirrhosis of liver (HR, 2.285; PFDR  = 0.002), being significantly associated with a higher risk of incident ACD. Restricted cubic spline models identified a strong U-shaped association between Alb and AST and incident ACD (Pnonlinear  <0.05). Worse cognition was positively correlated with AST, AST to ALT ratio, direct bilirubin (DBil), and GGT; negatively correlated with ALT, Alb, and total bilirubin (TBil); and ALD and fibrosis and cirrhosis of liver (PFDR  <0.05). Moreover, changes in ALT, GGT, AST to ALT ratio, and ALD were significantly associated with altered cortical and subcortical regions, including hippocampus, amygdala, thalamus, pallidum, and fusiform (PFDR  <0.05). In sensitivity analysis, metabolic dysfunction-associated steatotic liver disease (MASLD) was associated with the risk of ACD and brain subcortical changes. Our findings provide substantial evidence that liver dysfunction may be an important factor for incident dementia. Early intervention in the unhealthy liver may help prevent cognitive impairment and dementia incidence.

Neovascularization is a critical process in tumor progression and malignant transformation associated with neurofibromatosis type 1 (NF1). Indeed, fibroblasts are known to play a key role in the tumoral microenvironment modification by producing an abundant collagenous matrix, but their contribution in paracrine communication pathways is poorly understood. Here, we hypothesized that NF1 heterozygosis in human dermal fibroblasts could promote angiogenesis through exosomes secretion. The purposes of this study are to identify the NF1 fibroblast-derived exosome protein contents and to determine their proangiogenic activity. Angiogenic proteome measurement confirmed the overexpression of VEGF and other proteins involved in vascularization. Tube formation of microvascular endothelial cells was also enhanced in presence of exosomes derived from NF1 skin fibroblasts. NF1 tissue-engineered skin (NF1-TES) generation showed a significantly denser microvessels networks compared to healthy controls. The reduction of exosomes production with an inhibitor treatment demonstrated a drastic decrease in blood vessel formation within the dermis. Our results suggest that NF1 haploinsufficiency alters the dermal fibroblast function and creates a pro-angiogenic signal via exosomes, which increases the capillary formation. This study highlights the potential of targeting exosome secretion and angiogenesis for therapeutic interventions in NF1.

Chronic cerebral hypoperfusion leads to sustained demyelination and a unique response of microglia. Triggering receptor expressed on myeloid cells 2 (Trem2), which is expressed exclusively on microglia in the central nervous system (CNS), plays an essential role in microglial response in various CNS disorders. However, the specific role of Trem2 in chronic cerebral hypoperfusion has not been elucidated. In this study, we investigated the specific role of Trem2 in a mouse model of chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis (BCAS). Our results showed that chronic hypoperfusion induced white matter demyelination, microglial phagocytosis, and activation of the microglial autophagic-lysosomal pathway, accompanied by an increase in Trem2 expression. After Trem2 knockout, we observed attenuation of white matter lesions and microglial response. Trem2 deficiency also suppressed microglial phagocytosis and relieved activation of the autophagic-lysosomal pathway, leading to microglial polarization towards anti-inflammatory and homeostatic phenotypes. Furthermore, Trem2 knockout inhibited lipid droplet accumulation in microglia invitro. Collectively, these findings suggest that Trem2 deficiency ameliorated microglial phagocytosis and autophagic-lysosomal activation in hypoperfusion-induced white matter injury, and could be a promising target for the treatment of chronic cerebral hypoperfusion.

NADPH oxidase (Nox), a major source of reactive oxygen species (ROS), is involved in neurodegeneration after injury and disease. Nox is expressed in both neuronal and non-neuronal cells and contributes to an elevated ROS level after injury. Contrary to the well-known damaging effect of Nox-derived ROS in neurodegeneration, recently a physiological role of Nox in nervous system development including neurogenesis, neuronal polarity, and axonal growth has been revealed. Here, we tested a role for neuronal Nox in neurite regeneration following mechanical transection in cultured Aplysia bag cell neurons. Using a novel hydrogen peroxide (H2 O2 )-sensing dye, 5'-(p-borophenyl)-2'-pyridylthiazole pinacol ester (BPPT), we found that H2 O2 levels are elevated in regenerating growth cones following injury. Redistribution of Nox2 and p40phox in the growth cone central domain suggests Nox2 activation after injury. Inhibiting Nox with the pan-Nox inhibitor celastrol reduced neurite regeneration rate. Pharmacological inhibition of Nox is correlated with reduced activation of Src2 tyrosine kinase and F-actin content in the growth cone. Taken together, these findings suggest that Nox-derived ROS regulate neurite regeneration following injury through Src2-mediated regulation of actin organization in Aplysia growth cones.

Amyloid-β (Aβ) and hyper-phosphorylated tau are key hallmarks of Alzheimer's disease (AD), with an accumulation of both proteins linked to hippocampal synaptic dysfunction. Recent evidence indicates that Aβ drives mis-localisation of tau from axons to synapses, resulting in AMPA receptor (AMPAR) internalisation and impaired excitatory synaptic function. These tau-driven synaptic impairments are thought to underlie the cognitive deficits in AD. Consequently, limiting the synapto-toxic effects of tau may prevent AD-related cognitive deficits. Increasing evidence links leptin dysfunction with higher AD risk, and numerous studies have identified neuroprotective properties of leptin in AD models of Aβ-induced toxicity. However, it is unclear if leptin protects against tau-related synaptic dysfunction. Here we show that Aβ1-42 significantly increases dendritic and synaptic levels of tau and p-tau in hippocampal neurons, and these effects were blocked by leptin. In accordance with GSK-3β being involved in tau phosphorylation, the protective effects of leptin involve PI 3-kinase (PI3K) activation and inhibition of GSK-3β. Aβ1-42 -driven synaptic targeting of tau was associated with the removal of GluA1-containing AMPARs from synapses, which was also inhibited by leptin-driven inhibition of GSK-3β. Direct application of oligomeric tau to hippocampal neurons caused internalisation of GluA1-containing AMPARs and this effect was blocked by prior application of leptin. Similarly, leptin prevented the ability of tau to block induction of activity-dependent long-term potentiation (LTP) at hippocampal SC-CA1 synapses. These findings increase our understanding of the neuroprotective actions of leptin in the early pre-clinical stages of AD and further validate the leptin system as a therapeutic target in AD.

Voltage-gated calcium channels (VGCC) are abundant in the central nervous system and serve a broad spectrum of functions, either directly in cellular excitability or indirectly to regulate Ca2+ homeostasis. Ca2+ ions act as one of the main connections in excitation-transcription coupling, muscle contraction and excitation-exocytosis coupling, including synaptic transmission. In recent years, many genes encoding VGCCs main α or additional auxiliary subunits have been associated with epilepsy. This review sums up the current state of knowledge on disease mechanisms and provides guidance on disease-specific therapies where applicable.

Cerebral malaria (CM), a potentially fatal encephalopathy caused primarily by infection with Plasmodium falciparum, results in long-term adverse neuro-psychiatric sequelae. Neural cell injury contributes to the neurological deficits observed in CM. Abnormal regulation of tau, an axonal protein pathologically associated with the formation of neurofibrillary lesions in neurodegenerative diseases, has been linked to inflammation and cerebral microvascular compromise and has been reported in human and experimental CM (ECM). Immunotherapy with a monoclonal antibody to pathological tau (PHF-1 mAB) in experimental models of neurodegenerative diseases has been reported to mitigate cognitive decline. We investigated whether immunotherapy with PHF-1 mAB prevented cerebral endotheliopathy, neural cell injury, and neuroinflammation during ECM. Using C57BL/6 mice infected with either Plasmodium berghei ANKA (PbA), which causes ECM, Plasmodium berghei NK65 (PbN), which causes severe malaria, but not ECM, or uninfected mice (Un), we demonstrated that when compared to PbN infection or uninfected mice, PbA infection resulted in significant memory impairment at 6 days post-infection, in association with abnormal tau phosphorylation at Ser202 /Thr205 (pSer202 /Thr205 ) and Ser396-404 (pSer396-404 ) in mouse brains. ECM also resulted in significantly higher expression of inflammatory markers, in microvascular congestion, and glial cell activation. Treatment with PHF-1 mAB prevented PbA-induced cognitive impairment and was associated with significantly less vascular congestion, neuroinflammation, and neural cell activation in mice with ECM. These findings suggest that abnormal regulation of tau protein contributes to cerebral vasculopathy and is critical in the pathogenesis of neural cell injury during CM. Tau-targeted therapies may ameliorate the neural cell damage and subsequent neurocognitive impairment that occur during disease.

Significant evidence suggests that misfolded alpha-synuclein (aSyn), a major component of Lewy bodies, propagates in a prion-like manner contributing to disease progression in Parkinson's disease (PD) and other synucleinopathies. In fact, timed inoculation of M83 hemizygous mice with recombinant human aSyn preformed fibrils (PFF) has shown symptomatic deficits after substantial spreading of pathogenic alpha-synuclein, as detected by markers for the phosphorylation of S129 of aSyn. However, whether accumulated toxicity impact human-relevant cognitive and structural neuroanatomical measures is not fully understood. Here we performed a single unilateral striatal PFF injection in M83 hemizygous mice, and using two assays with translational potential, ex vivo magnetic resonance imaging (MRI) and touchscreen testing, we examined the combined neuroanatomical and behavioral impact of aSyn propagation. In PFF-injected mice, we observed widespread atrophy in bilateral regions that project to or receive input from the injection site using MRI. We also identified early deficits in reversal learning prior to the emergence of motor symptoms. Our findings highlight a network of regions with related cellular correlates of pathology that follow the progression of aSyn spreading, and that affect brain areas relevant for reversal learning. Our experiments suggest that M83 hemizygous mice injected with human PFF provides a model to understand how misfolded aSyn affects human-relevant pre-clinical measures and suggest that these pre-clinical biomarkers could be used to detect early toxicity of aSyn and provide better translational measures between mice and human disease.