ABSTRACT

Selective elimination of early pathological TAU species may be a promising therapeutic strategy to reduce TAU accumulation that contributes to neurodegeneration and hallmarks Alzheimer disease (AD). By performing a genetic analysis of a cohort of 435 patients with AD, we defined the NDP52GE variant (rs550510) of the autophagic receptor NDP52 (also known as CALCOCO2) as a protective factor for AD. We provide evidence that in in vitro systems and in a Drosophila melanogaster model of TAU-induced AD, NDP52 reduces the accumulation of pathological forms of TAU through the autophagic process and rescues typical neurodegenerative phenotypes induced by hTAU-toxicity. More importantly, we showed that the NDP52GE variant is much more effective in this respect than NDP52WT. Mechanistically, we showed that NDP52 directly binds pathological phospho-TAU, and that NDP52WT and NDP52GE bind them with comparable efficiency. On the contrary, we showed that NDP52GE binds the autophagic machinery (LC3C and LC3B) more efficiently than NDP52WT. We also showed for the first time that NDP52 is a direct target of protein phosphatase 2A (PP2A) in vitro, opening the way to the possibility that this phosphatase may fine-tune the autophagic function of NDP52 in AD. Finally, we found a positive correlation between the worldwide distribution of the allele encoding NDP52GE and the incidence or prevalence of AD. Overall, our work highlights the variant NDP52GE as a resilience factor in AD that shows a robust effectiveness to drive pathological TAU degradation.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This work was supported by AIRC Foundation (Grant IG MFAG-2020 24467), AIRAlzh (Associazione Italiana Ricerca Alzheimer Onlus) Grant for Young Researchers - AGYR 2020 and France Alzheimer to FS. CG and MC thank the Veneto Region - Biological Bases of Alzheimer's Disease (BioMA) Project. V. Cianfanelli is supported by the MIUR-Italy Departments of Excellence 2023-2027 to the Dept. of Science (Univ. Roma Tre) and the GR-2021-12372771 from the Italian Ministry of Health.

Author Declarations

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The study cohort overall involved 434 patients affected by sporadic AD and 1000 healthy subjects as control group. In particular, blood samples from 189 AD patients and 1000 control subjects already stored in the Genomic Medicine Laboratory of Santa Lucia Foundation IRCCS were analyzed. Briefly, these patients were recruited from 2010 to 2021 at the Outpatient Memory Clinic of the Laboratory of Neuropsychiatry of IRCCS Santa Lucia Foundation, Rome, Italy. The diagnosis of sporadic AD dementia was based on medical history and neurological examination, including brain imaging and instrumental tests, overall fulfilling the clinical criteria of the National Institute on Aging and the Alzheimer Association. These patients were enrolled for a previous study approved by the Ethical committee (CE/PROG.650 approved on 01/03/2018) of IRCCS Santa Lucia Foundation Hospital of Rome and in accordance with the Declaration of Helsinki. A written informed consent of the study was obtained for all patients and control subjects. In addition, blood samples from 245 AD untreated patients were collected from 245 untreated patients admitted to the memory clinic of CRIC in Padua between April 2001 and March 2018. Diagnosis of late onset non-familial AD was made, according to internationally established criteria. The diagnosis was obtained at the end of the diagnostic protocol by clinical, laboratory, and neuropsychological assessment, all subjects underwent CT or MR neuroimaging and 84/245 were further characterized after PET scanning or CSF biomarkers evaluation. All peripheral blood samples were collected after obtaining the written informed consent of the study participants, in accordance with the Helsinki Declaration. The study protocol Analisi delle Basi Biologiche della Malattia di Alzheimer eredofamiliare e delle forme sporadiche tardive (3950/AO/2016) was approved by the local ethic committee of the recruitment center on October 06th 2016.

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Data Availability

All data produced in the present study are available upon reasonable request to the authors

ABBREVIATIONSADAlzheimer Disease;ATG8Autophagy-related protein 8;cLIRnon-canonical LC3 interacting region;LIRLC3 interacting region;NDP52Nuclear Dot Protein 52, also known asCALCOCO2calcium binding and coiled-coil domain 2;OkAOkadaic Acid;PP2Aprotein phosphatase 2A;pTAUphospho-TAU.