The cell adhesion molecule neuroplastin (Np) is a novel candidate to influence human intelligence. Np-deficient mice display complex cognitive deficits and reduced levels of Plasma Membrane Ca²⁺ ATPases (PMCAs), an essential regulator of the intracellular Ca²⁺ concentration ([iCa²⁺]) and neuronal activity. We show abundant expression and conserved cellular and molecular features of Np in glutamatergic neurons in human hippocampal-cortical pathways as characterized for the rodent brain. In Nptn ^{lox/loxEmx1Cre} mice, glutamatergic neuron-selective Np ablation resulted in behavioral deficits indicating hippocampal, striatal, and sensorimotor dysfunction paralleled by highly altered activities in hippocampal CA1 area, sensorimotor cortex layers I-III/IV, and the striatal sensorimotor domain detected by single-photon emission computed tomography. Altered hippocampal and cortical activities correlated with reduction of distinct PMCA paralogs in Nptn ^{lox/loxEmx1Cre} mice and increased [iCa²⁺] in cultured mutant neurons. Human and rodent Np enhanced the post-transcriptional expression of and co-localized with PMCA paralogs in the plasma membrane of transfected cells. Our results indicate Np as essential for PMCA expression in glutamatergic neurons allowing proper [iCa²⁺] regulation and normal circuit activity. Neuron-type-specific Np ablation empowers the investigation of circuit-coded learning and memory and identification of causal mechanisms leading to cognitive deterioration.

Neuroinflammation is one of the core pathological features of Alzheimer’s disease (AD) as both amyloid β (Aβ) and tau monomers and oligomers can trigger the long-term pro-inflammatory phenotype of microglial cells with consequent overactivation of the inflammasomes. To investigate the NLRP1 inflammasome activation in AD, we analyzed the expression of NLRP1, ASC, cleaved gasdermin (cGSDMD), and active caspase-6 (CASP-6) proteins in each hippocampal subdivision (hilar part of CA3, CA2/3, CA1, subiculum) of postmortem tissue of 9 cognitively healthy controls (HC) and 11 AD patients whose disease duration varied from 3 to 7 years after the clinical diagnosis. The total number of neurons, along with the total number of neurofibrillary tangles (NFTs), were estimated in Nissl- and adjacent modified Bielschowsky-stained sections, respectively, using the optical disector method. The same 9 HC and 11 AD cases were additionally semiquantitatively analyzed for expression of IBA1, HLA-DR, and CD68 microglial markers. Our results show that the expression of NLRP1, ASC, and CASP-6 is present in a significantly greater number of hippocampal formation neurons in AD brains compared to controls, suggesting that the NLRP1 inflammasome is more active in the AD brain. None of the investigated inflammasome and microglial markers were found to correlate with the age of the subjects or the duration of AD. However, besides positive correlations with microglial IBA1 expression in the subiculum and with microglial CD68 expression in the CA1 field and subiculum in the AD group, the overall NLRP1 expression in the hippocampal formation was positively correlated with the number of NFTs, thus providing a causal link between neuroinflammation and neurofibrillary degeneration. The accumulation of AT8-immunoreactive phosphorylated tau proteins that we observed at nuclear pores of large pyramidal neurons of the Ammon’s horn further supports their role in the extent of neuronal dysfunction and degeneration in AD. This is important because unlike fibrillar amyloid-β deposits that are not related to dementia severity, total NFTs and neuron numbers in the hippocampal formation, especially in the CA1 field, are the best correlates of cognitive deterioration in both human brain aging and AD. Our findings also support the notion that the CA2 field vulnerability is strongly linked to specific susceptibilities to different tauopathies, including primary age-related tauopathy. Altogether, these findings contrast with reports of nonsignificant microglial activation in aged nonhuman primates and indicate that susceptibility to inflammasome activation may render the human brain comparatively more vulnerable to neurodegenerative changes and AD. In conclusion, our results confirm a key role of NLRP1 inflammasome in AD pathogenesis and suggest NLRP1 as a potential diagnostic marker and therapeutic target to slow or prevent AD progression.

Cell‐adhesion glycoprotein neuroplastin (Np) is involved in the regulation of synaptic plasticity and balancing hippocampal excitatory/inhibitory inputs which aids in the process of associative memory formation and learning. Our recent findings show that neuroplastin expression in the adult human hippocampus is specifically associated with major hippocampal excitatory pathways and is related to neuronal calcium regulation. Here, we investigated the hippocampal expression of brain‐specific neuroplastin isoform (Np65), its relationship with amyloid and tau pathology in Alzheimer's disease (AD), and potential involvement of neuroplastin in tissue response during the disease progression. Np65 expression and localization was analysed in six human hippocampi with confirmed AD neuropathology, and six age‐/gender‐matched control hippocampi by imunohistochemistry. In AD cases with shorter disease duration, the Np65 immunoreactivity was significantly increased in the dentate gyrus (DG), Cornu Ammonis 2/3 (CA2/3), and subiculum, with the highest level of Np expression being located on the dendrites of granule cells and subicular pyramidal neurons. Changes in the expression of neuroplastin in AD hippocampal areas seem to be related to the progression of disease. Our study suggests that cell‐adhesion protein neuroplastin is involved in tissue reorganization and is a potential molecular marker of plasticity response in the early neurodegeneration process of AD.

The recent identification of plasma membrane (Ca²⁺)-ATPase (PMCA)-Neuroplastin (Np) complexes has renewed attention on cell regulation of cytosolic calcium extrusion, which is of particular relevance in neurons. Here, we tested the hypothesis that PMCA-Neuroplastin complexes exist in specific ganglioside-containing rafts, which could affect calcium homeostasis. We analyzed the abundance of all four PMCA paralogs (PMCA1-4) and Neuroplastin isoforms (Np65 and Np55) in lipid rafts and bulk membrane fractions from GM2/GD2 synthase-deficient mouse brains. In these fractions, we found altered distribution of Np65/Np55 and selected PMCA isoforms, namely PMCA1 and 2. Cell surface staining and confocal microscopy identified GM1 as the main complex ganglioside co-localizing with Neuroplastin in cultured hippocampal neurons. Furthermore, blocking GM1 with a specific antibody resulted in delayed calcium restoration of electrically evoked calcium transients in the soma of hippocampal neurons. The content and composition of all ganglioside species were unchanged in Neuroplastin-deficient mouse brains. Therefore, we conclude that altered composition or disorganization of ganglioside-containing rafts results in changed regulation of calcium signals in neurons. We propose that GM1 could be a key sphingolipid for ensuring proper location of the PMCA-Neuroplastin complexes into rafts in order to participate in the regulation of neuronal calcium homeostasis.

Thy-1 is a small membrane glycoprotein and member of the immunoglobulin superfamily of cell adhesion molecules. It is abundantly expressed in many cell types including neurons and is anchored to the outer membrane leaflet via a glycosyl phosphatidylinositol tail. Thy-1 displays a number of interesting properties such as fast lateral diffusion, which allows it to get in and out of membrane nanodomains with different lipid composition. Thy-1 displays a broad expression in different cell types and plays confirmed roles in cell development, adhesion and differentiation. Here, we explored the functions of Thy-1 in neuronal signaling, initiated by extracellular binding of α_Vβ₃ integrin, may strongly dependent on the lipid content of the cell membrane. Also, we assort literature suggesting the association of Thy-1 with specific components of lipid rafts such as sialic acid containing glycosphingolipids, called gangliosides. Furthermore, we argue that Thy-1 positioning in nanodomains may be influenced by gangliosides. We propose that the traditional conception of Thy-1 localization in rafts should be reconsidered and evaluated in detail based on the potential diversity of neuronal nanodomains.