Neuronal lysosomal dysfunction releases exosomes harboring APP C-terminal fragments and unique lipid signatures

Defects in endolysosomal and autophagic functions are increasingly viewed as key pathological features of neurodegenerative disorders. A master regulator of these functions is phosphatidylinositol-3-phosphate (PI3P), a phospholipid synthesized primarily by class III PI 3-kinase Vps34. Here we report that disruption of neuronal Vps34 function in vitro and in vivo impairs autophagy, lysosomal degradation as well as lipid metabolism, causing endolysosomal membrane damage. PI3P deficiency also promotes secretion of unique exosomes enriched for undigested lysosomal substrates, including amyloid precursor protein C-terminal fragments (APP-CTFs), specific sphingolipids, and the phospholipid bis(monoacylglycero)phosphate (BMP), which normally resides in the internal vesicles of endolysosomes. Secretion of these exosomes requires neutral sphingomyelinase 2 and sphingolipid synthesis. Our results reveal a homeostatic response counteracting lysosomal dysfunction via secretion of atypical exosomes eliminating lysosomal waste and define exosomal APP-CTFs and BMP as candidate biomarkers for endolysosomal dysfunction associated with neurodegenerative disorders.Fan Wang for the kind gift of the Pi3kc3flox/flox mice. We thank Basant Abdulrahman and Hermann Schaetzl for providing the gene-edited Atg5 KO N2a cells. We are also grateful to Zhenyu Yue, Ralph Nixon, and Jean Gruenberg for the kind gift of anti-Atg14L, Cathepsin D, and BMP antibodies, respectively. We thank Thomas Südhof for sharing Cre recombinase lentiviruses. We thank the OCS Microscopy Core of New York University Langone Medical Center for the support of the EM work and Rocio Perez-Gonzalez and Efrat Levy of New York University for their support during optimization of the brain exosome isolation technique. We thank Elizabeta Micevska for the maintenance and genotyping of the animal colony and Bowen Zhou for the preliminary lipidomic analysis of conditional Pi3kc3 cKO mice. We also thank Rebecca Williams and Catherine Marquer for critically reading the manuscript. This work was supported by grants from the Fundação para a Ciência e Tecnologia (PD/BD/105915/2014 to A.M.M.); the National Institute of Health (R01 NS056049 to G.D.P., transferred to Ron Liem, Columbia University; T32-MH015174 to Rene Hen (Z.M.L.)). Z.M.L. and R.B.C. received pilot grants from ADRC grant P50 AG008702 to S.A.S.info:eu-repo/semantics/publishedVersio

História e memórias do banco de leite humano do Instituto de Medicina Integral Prof. Fernando Figueira (1987-2009) em Recife, Pernambuco, Brasil History and memories of the human milk bank of the Instituto de Medicina Integral Prof. Fernando Figueira (1987-2009) in Recife, Pernambuco, Brazil

OBJETIVOS: reconstituir a história do Banco de Leite Humano (BLH) do Instituto de Medicina Integral Professor Fernando Figueira (IMIP), enfocando os idealizadores e a inauguração do serviço. MÉTODOS: estudo descritivo, transversal com enfoque histórico, orientado pela metodologia da história oral. Privilegiou-se a consulta a fontes bi¬bliográficas e a entrevista direta a sete participantes, com roteiro estruturado. A análise das falas desvelou duas categorias: "Criação do banco de leite humano do IMIP: os idealizadores e suas influências"; e "A inauguração". RESULTADOS: o BLH do IMIP foi criado em 1987, com a idealização e o incentivo do Professor Fernando Figueira e da Dra. Vilneide Braga, e para suprir as necessidades da Maternidade e da unidade de terapia intensiva neonatal. Da inauguração, participaram autoridades políticas, autoridades em aleitamento materno, celebridades da mídia e profissionais do hospital. CONCLUSÕES: o entrelaçamento entre história e memória, conduzido pelas trilhas da história oral, foi matriz para a construção da origem e evolução do BLH do IMIP, a partir da fala de sujeitos envolvidos nos fatos. A história do BLH do IMIP é um processo inacabado, vivo, é uma força geradora de transformação, sonhos e esperança, que mantém aceso o ideal de um mundo melhor para as crianças, para as mães e para a sociedade.<br>OBJECTIVES: to recount the history of the Instituto de Medicina Integral Professor Fernando Figueira (IMIP)'s Human Milk Bank (HMB), focusing on its pioneers and the introduction of the service. METHODS: a descriptive transversal study with historical focus based on the methods of oral history. The main materials used were bibliographical sources and direct structured interviews with seven participants. Content analysis revealed two categories: "the Creation of the IMIP's Human Milk Bank: its pioneers and their influences"; and "the Introduction of the Service". RESULTS: the IMIP's HMB, set up in 1987, was the brainchild of Professor Fernando Figueira and Dr. Vilneide Braga and its aim was to meet the needs of the Maternity hospital and its neonatal intensive care unit. The inauguration was attended by politicians, breastfeeding experts, TV celebrities and hospital staff. CONCLUSIONS: the methods of oral history were used to build up a history of the origins and evolution of the IMIP's HMB based on the testimony of the individuals involved. The history of the IMIP's HMB is an ongoing, living process and force that produces change, dreams and hope and keeps alight the ideal of a better world for children, mothers and for society at large