Biology subjects

Frigeri, A.

Publications and source records attributed to Frigeri, A..

3 recordsLinked to original sources

bioRxiv2025

Neurodegeneration in the olfactory system in Niemann Pick type C1 disease

Niemann-Pick type C1 (NPC1) disease is a rare neurodegenerative disorder linked to defective cholesterol biosynthesis and altered lipid regulation. In patients, the most common variant in the Npc1 gene is a missense mutation that leads to a misfolded and non-functional NPC1 protein. We used a mouse model carrying this mutation (I1061T, Npc1tm(I1061T)Dso) to investigate the olfactory system since olfaction is often negatively impacted in many neurodegenerative disorders, with olfactory decline frequently preceding other neurodegenerative symptoms. We characterized cell types in the olfactory epithelium (OE) in wild-type, heterozygous, and homozygous Npc1tm(I1061T)Dso mice to analyze neurodegeneration at two time points, namely 36 and 60 days after birth. In homozygous Npc1tm(I1061T)Dso mice the density of olfactory sensory neurons (OSNs) at 36 days after birth is decreased compared to wild type and heterozygous mice while the density of immature OSNs and the stem cell niche seems to not be affected. In the OE of the homozygous Npc1tm(I1061T)Dso mice we found an increased density of apoptotic cells and clear sign of neuroinflammation in macrophage/microglia infiltrating the OE. We analyzed the lipid profile of OE by positive MALDI-TOF and found increased markers of neuroinflammation homozygous Npc1tm(I1061T)Dso mice. These structural changes affected the functionality of the OE since we found reduced odorant responses in Npc1tm(I1061T)Dso mice compared to wild type. Additionally, our olfactory behavioral tests revealed deficits in odor-guided food-seeking tests in Npc1tm(I1061T)Dso but not in the wild type and heterozygous mice. We also analyzed the olfactory abilities of a family of three with the parents carrying two different mutations of the Npc1 gene, with the child carrying both mutations and being diagnosed with NPC1 disease. Using the Sniffin Sticks olfactory test, we found that all three were hyposmic with the child having severe hyposmia. Our work extensively characterized the OE structurally and functionally proposing it as a sentinel to monitor disease progression. We are the first to show that NPC1 patients are affected by severe hyposmia and that heterozygous parents could be monitored for olfactory abilities since it could be a biomarker for future neurological disorders.

neuroscience↗

bioRxiv2024

Aquaporin-4 expression levels and mis-localization are inversely linked to peritumoral edema in gliomas of varying aggressiveness

Aquaporin-4 (AQP4) and its extended isoform, AQP4ex, are crucial for regulating brain water homeostasis. Mis-localization of these isoforms is implicated in various brain tumors, including glioblastoma multiforme (GBM). This study explores AQP4 isoform expression and localization in Pilocytic Astrocytomas (PA), a circumscribed astrocytic low-grade glioma, compared to GBM, an adult-type diffuse high grade glioma. We found significant upregulation of AQP4 and AQP4ex in PA, with notable mis-localization deviating from the typical perivascular localization seen in healthy tissue. This mis-localization mirrors the phenotype observed in AQP4ex knockout models, where impaired AQP4 localization is linked to disrupted water homeostasis and reduced waste clearance, despite overall increased AQP4 levels. Interestingly, PA shows minimal peritumoral edema and a relatively intact blood-brain barrier (BBB), with elevated phosphorylated AQP4ex (pAQP4ex) suggesting a role in stabilizing AQP4 function. In contrast, GBM exhibits reduced AQP4/AQP4ex expression, significant peritumoral edema, and BBB disruption. GFAP isoforms, GFAP{kappa} and GFAP{delta}, are upregulated in PA, associated with Rosenthal fibers, indicating a stabilizing astrocytic response. GBM, however, shows generalized GFAP increase, reflecting aggressive gliosis and disrupted water homeostasis. In conclusion, both AQP4 expression levels and mis-localization are important factors influencing peritumoral edema and tumor aggressiveness in gliomas. This study positions AQP4 as a potential biomarker for glioma progression, offering insights into astrocytic function and paving the way for targeted therapies.

cancer biology↗

bioRxiv2024

The Aquaporin-4 expression and localization in the olfactory epithelium modulate the odorant-evoked responses and olfactory driven behavior

Aquaporin-4 (AQP4) is a water-selective channel expressed in glial cells throughout the central nervous system. It serves as the main water channel in the neuropil, and is involved in various physiological functions, ranging from regulating water homeostasis by adjusting cell volume to modulating neuronal activity. Different isoforms of AQP4 are expressed in glial-like cells known as sustentacular cells (SUSs) of the olfactory epithelium (OE). Interestingly, mice lacking all AQP4 isoforms exhibit impaired olfactory abilities. Hence, we aim to uncover the physiological role of two AQP4 isoforms, the perivascular AQP4ex isoform and the Orthogonal Array of Particle (OAP)-forming isoform (AQP4M23) in the OE. Primarily, we investigated the impact of AQP4 isoforms on OE protein expression, finding reduced levels of mature olfactory sensory neurons (OSNs) in mice lacking AQP4ex (AQP4ex-KO) or OAPs (OAP-null). Moreover, the reduced number of OSNs, SUSs, and globose basal cells (GBCs) suggests that AQP4 isoforms are involved in maintaining an optimal microenvironment in the OE, preserving the overall cell density. Then, we explored the role of AQP4 in modulating odorant-evoked responses through electro-olfactogram recordings, finding reduced odorant responses in mice lacking AQP4 isoforms. Olfactory ability assessments revealed deficits in odor-guided food-seeking test in AQP4ex-KO and OAP-null mice. Furthermore, AQP4ex-KO mice showed a reduced ability to discriminate between different odorants, while OAP-null mice were unable to recognize them as distinct. Overall, our data highlight the role of AQP4 isoforms in modulating neuronal homeostasis, affecting odorant-evoked responses and cell density in the OE. These results shed light on SUSs involvement in mediating these processes and establish a foundation for further understanding their role in controlling OE physiology.

neuroscience↗