Peripheral immune priming can induce long-lasting changes in brain innate immune responses. In neurological diseases, including Alzheimer’s disease and stroke, inflammatory priming has been associated with neuroprotection, likely through microglial reprogramming. Here, we evaluated whether repeated peripheral histamine exposure was associated with persistent glial morphometric remodelling and with an altered response to subsequent dopaminergic injury. Adult male mice received four consecutive daily intraperitoneal injections of histamine, lipopolysaccharide (LPS), used as a reference peripheral immune-stimulating condition, or PBS. Three weeks later, glial morphometry was assessed in the substantia nigra (SN) and striatum (ST). In a separate cohort, mice underwent intrastriatal 6-hydroxydopamine (6-OHDA) lesion three weeks after priming. Motor behaviour, nigrostriatal TH immunoreactivity, apomorphine-evoked striatal neuronal recruitment and glial morphometric response were evaluated two weeks later. Under non-lesioned conditions, histamine and LPS exposure were associated with persistent microglial morphometric remodelling in the SN, whereas comparable ST changes were detected only after LPS. Astrocytic GFAP-based measures showed modest, non-significant trends in the SN. Following 6-OHDA lesion, prior histamine or LPS exposure reduced apomorphine-induced rotational asymmetry and was associated with greater preservation of tyrosine hydroxylase (TH) immunoreactivity in the nigrostriatal system. Histamine priming additionally increased apomorphine-evoked recruitment of DARPP-32-positive striatal neurons and attenuated lesion-associated microglial changes in the SN and ST. Astrocytic responses after lesion were region-dependent. Repeated peripheral histamine exposure was associated with persistent, region-specific glial morphometric remodelling and attenuated behavioural and dopaminergic deficits following subsequent 6-OHDA injury. These findings are compatible with long-lasting histamine-associated neuroimmune conditioning, although the underlying cellular and molecular mechanisms and the causal contribution of glial remodelling remain to be established. Repeated peripheral histamine or LPS exposure is associated with long-lasting, region-specific glial remodelling and attenuated 6-OHDA-induced dopaminergic injury.
Protein-misfolding neuropathic diseases are characterized by the accumulation in the central nervous system of misfolded proteins, whose irreversible change into beta-sheets sticky conformation facilitates the protein to form aggregates, which represent the main commonality shared by these disorders, including Prion diseases, Alzheimer’s disease, Parkinson's disease, Amyotrophic lateral sclerosis and Frontotemporal dementia. To explain the mechanisms through which protein misfolding and aggregation lead to the development of these diseases, at least three models have been proposed. Besides the widely accepted gain- or loss-of-function model for misfolded proteins, the inflammation model proposes that abnormal protein aggregates act as culprits causing chronic inflammatory response that leads to cell death. Historically, inflammatory events were viewed as result of toxicity from the inability of the cell to clear misfolded proteins. However, how misfolded proteins cause inflammation remains still an open issue. Given the current lack of an overarching view describing the connection between protein misfolding-related neurodegenerative diseases and the inflammasome, we aim to outline this relationship in the present review. We integrate recent insights into the mechanistic links between protein misfolding and NLRP3 inflammasome activation, highlighting the impact of the recently described “prionoid-activity” of ASC specks on the progression of different neurodegenerative misfolding diseases.
Depression is a common mood disorder with limited treatment efficacy. N-myc downstream-regulated gene 2 (NDRG2) is a stress-responsive molecule expressed in astrocytes and has been recognized as a key regulator in depression; however, its underlying mechanisms remain largely unclear. This review summarizes the current evidence and highlights two important points. First, NDRG2 integrates multiple well-established depression-related pathways—including astrocyte apoptosis, neuroinflammation, hypothalamic-pituitary-adrenal (HPA) axis dysfunction, synaptic plasticity, glutamate homeostasis, neurogenesis, mitochondrial dysfunction, and brain-blood barrier (BBB) dysfunction—into a coordinated regulatory network. Second, NDRG2 exhibits dual effects depending on the pathological context, suggesting that targeting it may offer a more precise therapeutic strategy than approaches that modulate single pathways. By proposing an NDRG2-centered network model for depression, this review provides a new conceptual framework for understanding the disease and positions NDRG2 as a promising yet challenging therapeutic target. Further studies are needed to clarify its precise molecular mechanisms and evaluate its translational potential.
Although amyotrophic lateral sclerosis (ALS) has traditionally been viewed as a motor neuron-centered disease manifesting by muscle wasting and weakness, growing evidence indicates that disease progression is strongly influenced by interactions between motor neurons and surrounding glial cells. Astrocytes are major regulators of lipid metabolism in the brain, managing cholesterol synthesis, fatty acid detoxification, lipid trafficking and storage, and redox balance. Neurons, which have limited lipid-handling capacity, rely on astrocytes to maintain a safe lipid environment. In addition to their well-established roles in neurotransmitter recycling, metabolic support, excitotoxicity, and blood–brain barrier maintenance, astrocytes contribute to ALS through multiple pathogenic mechanisms. This review focuses specifically on disturbances in lipid metabolism, an emerging aspect of astrocyte biology that has received comparatively less attention. Evidence from human neuropathology, lipidomics, genetics, and ALS models suggests that altered astrocytic lipid homeostasis contributes to motor neuron vulnerability and disease progression. Altered cholesterol metabolism, impaired peroxisomal function, defective lipid droplet dynamics, disrupted sphingolipid homeostasis, and compromised metabolic support have been linked to key disease processes, including TDP-43 pathology, mitochondrial and lysosomal dysfunction, excitotoxicity, oxidative stress, and neuroinflammation. Rather than representing a single initiating mechanism, astrocytic lipid dysregulation may constitute a convergent amplifying node through which diverse ALS-associated insults modify the neuronal microenvironment and increase vulnerability to degeneration. The contribution of astrocytic lipid dysregulation to ALS therefore provides a framework for understanding how metabolic disturbances may amplify motor neuron injury and disease progression, while identifying emerging opportunities to therapeutically target these pathways. Astrocytes are the principal regulators of lipid homeostasis in the central nervous system, and mounting evidence implicates disruption of these pathways as a key contributor to amyotrophic lateral sclerosis pathogenesis. This review examines current knowledge of astrocyte lipid metabolism, integrating findings from genetics, lipidomics, and human stem cell models to highlight emerging therapeutic opportunities targeting glial lipid biology. Created with BioRender.com.
Cell adhesion molecule 1 (CADM1) is an intercellular adhesion molecule belonging to the immunoglobulin superfamily that is abundantly expressed in the olfactory epithelium. Previously, we demonstrated efficient intracellular drug delivery to CADM1-expressing tumor cells using anti-CADM1 antibodies. In this study, we explored the potential of anti-CADM1 antibodies as a cargo for nose-to-brain (N2B) delivery of antitumor agents in mice. CADM1 expression and distribution in the mouse olfactory epithelium were confirmed by immunoblotting and immunohistochemistry. In the mouse nasal cavity, CADM1 is distributed in the olfactory epithelium and is prominent in the sustentacular cell layer of the olfactory epithelia. When CADM1 antibodies that recognize extracellular domain of CADM1 (3E1 and 9D2) were administered intranasally to mice, 3E1 exhibited both prolonged retention and greater accumulation specifically in the olfactory epithelium compared to a non-targeting control antibody. To quantitatively evaluate N2B drug delivery, we developed a simple and highly sensitive liquid chromatography–tandem mass spectrometry method capable of detecting monomethyl auristatin E (MMAE) in brain tissue at concentrations as low as 0.5 fmol/mg tissue. Using this method, the MMAE concentrations in the olfactory bulbs were quantified following intranasal administration of 3E1-MMAE. 3E1-mediated delivery resulted in significantly higher MMAE concentrations than those achieved with the control antibody on both days 4 (22.8 vs. 13.4 fmol/mg tissue) and 8 (19.0 vs. 14.7 fmol/mg tissue). These findings provide the first evidence that targeting a specific cell-surface protein in the olfactory epithelium can improve N2B drug delivery, offering a promising strategy for developing intranasal therapeutics. CADM1 targeting enhances nose-to-brain delivery of MMAE. Anti-CADM1 antibody (3E1) enhances nose-to-brain delivery of monomethyl auristatin E (MMAE) by targeting the olfactory epithelium. LC–MS/MS quantified increased MMAE accumulation in the olfactory bulb. Created with BioRender
