Genetic deletion of astrocytic calcineurin B1 prevents cognitive impairment and neuropathology development in acute and chronic mouse models of Alzheimer's disease Laura Tapella, Giulia Dematteis, Pietro La Vitola, Susanna Leva, Elisa Tonelli, et al. GLIA, 2024 Alzheimer's disease (AD) represents an urgent yet unmet challenge for modern society, calling for exploration of innovative targets and therapeutic approaches. Astrocytes, main homeostatic cells in the CNS, represent promising cell‐target. Our aim was to investigate if deletion of the regulatory CaNB1 subunit of calcineurin in astrocytes could mitigate AD‐related memory deficits, neuropathology, and neuroinflammation. We have generated two, acute and chronic, AD mouse models with astrocytic CaNB1 ablation (ACN‐KO). In the former, we evaluated the ability of β‐amyloid oligomers (AβOs) to impair memory and activate glial cells once injected in the cerebral ventricle of conditional ACN‐KO mice. Next, we generated a tamoxifen‐inducible astrocyte‐specific CaNB1 knock‐out in 3xTg‐AD mice (indACNKO‐AD). CaNB1 was deleted, by tamoxifen injection, in 11.7‐month‐old 3xTg‐AD mice for 4.4 months. Spatial memory was evaluated using the Barnes maze; β‐amyloid plaques burden, neurofibrillary tangle deposition, reactive gliosis, and neuroinflammation were also assessed. The acute model showed that ICV injected AβOs in 2‐month‐old wild type mice impaired recognition memory and fostered a pro‐inflammatory microglia phenotype, whereas in ACN‐KO mice, AβOs were inactive. In indACNKO‐AD mice, 4.4 months after CaNB1 depletion, we found preservation of spatial memory and cognitive flexibility, abolishment of amyloidosis, and reduction of neurofibrillary tangles, gliosis, and neuroinflammation. Our results suggest that ACN is crucial for the development of cognitive impairment, AD neuropathology, and neuroinflammation. Astrocyte‐specific CaNB1 deletion is beneficial for both the abolishment of AβO‐mediated detrimental effects and treatment of ongoing AD‐related pathology, hence representing an intriguing target for AD therapy.
Cell-Free and In Vivo Characterization of the Inhibitory Activity of Lavado Cocoa Flavanols on the Amyloid Protein Ataxin-3: Toward New Approaches against Spinocerebellar Ataxia Type 3 Barbara Sciandrone, Alessandro Palmioli, Carlotta Ciaramelli, Roberta Pensotti, Laura Colombo, et al. ACS Chemical Neuroscience, 2024 Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder characterized by ataxia and other neurological manifestations, with a poor prognosis and a lack of effective therapies. The amyloid aggregation of the ataxin-3 protein is a hallmark of SCA3 and one of the main biochemical events prompting its onset, making it a prominent target for the development of preventive and therapeutic interventions. Here, we tested the efficacy of an aqueous Lavado cocoa extract and its polyphenolic components against ataxin-3 aggregation and neurotoxicity. The combination of biochemical assays and atomic force microscopy morphological analysis provided clear evidence of cocoa flavanols' ability to hinder ATX3 amyloid aggregation through direct physical interaction, as assessed by NMR spectroscopy. The chemical identity of the flavanols was investigated by ultraperformance liquid chromatography-high-resolution mass spectrometry. The use of the preclinical model Caenorhabditis elegans allowed us to demonstrate cocoa flavanols' ability to ameliorate ataxic phenotypes in vivo. To the best of our knowledge, Lavado cocoa is the first natural source whose extract is able to directly interfere with ATX3 aggregation, leading to the formation of off-pathway species.