Alterations of neuronal lysosomes in Alzheimer's disease and in APPxPS1-KI mice

Alexandre Androuin (1, 2, 3) , Manon Thierry (1, 2) , Susana Boluda (1, 2) , Asha Baskaran (1, 2) , Dominique Langui (1, 2) , Charles Duyckaerts (1, 2) , Marie-Claude Potier (1, 2) , Khalid Hamid El Hachimi (1, 2) , Benoît Delatour (1, 2) , Serge Marty (1, 2)

1 ICM - Institut du Cerveau = Paris Brain Institute
2 CHU Pitié-Salpêtrière [AP-HP]
3 IPNP - U1266 Inserm - Institut de psychiatrie et neurosciences de Paris

Background: The cellular and molecular alterations associated with synapse and neuron loss in Alzheimer's disease (AD) remain unclear. In transgenic mouse models that express mutations responsible for familial AD, neuronal and synaptic losses occur in populations that accumulate fibrillar amyloid-β 42 (Aβ42) intracellularly. Objective: We aimed to study the subcellular localization of these fibrillar accumulations and whether such intraneuronal assemblies could be observed in the human pathology. Methods: We used immunolabeling and various electron microscopy techniques on APP x presenilin1 - knock-in mice and on human cortical biopsies and postmortem samples. Results: We found an accumulation of Aβ fibrils in lipofuscin granule-like organelles in APP x presenilin1 - knock-in mice. Electron microscopy of human cortical biopsies also showed an accumulation of undigested material in enlarged lipofuscin granules in neurons from AD compared to age-matched non-AD patients. However, in those biopsies or in postmortem samples we could not detect intraneuronal accumulations of Aβ fibrils, neither in the lipofuscin granules nor in other intraneuronal compartments. Conclusion: The intralysosomal accumulation of Aβ fibrils in specific neuronal populations in APPxPS1-KI mice likely results from a high concentration of Aβ42 in the endosome-lysosome system due to the high expression of the transgene in these neurons.

Mots clés: Alzheimer’s disease; amyloid-β; electron microscopy; lysosome

Domaines: Sciences du Vivant [q-bio]

Alexandre Androuin, Manon Thierry, Susana Boluda, Asha Baskaran, Dominique Langui, et al.. Alterations of neuronal lysosomes in Alzheimer's disease and in APPxPS1-KI mice. Journal of Alzheimer's Disease, 2022, ⟨10.3233/JAD-215692⟩. ⟨hal-03797416⟩