Alterations of Neuronal Lysosomes in Alzheimer’s Disease and in APPxPS1-KI Mice

Article type: Research Article

Authors: Androuin, Alexandre^{a; 1; *} | Thierry, Manon^a | Boluda, Susana^{a; b} | Brainbank NeuroCEB Neuropathology Network^c | Baskaran, Asha^a | Langui, Dominique^a | Duyckaerts, Charles^a | Potier, Marie-Claude^a | El Hachimi, Khalid Hamid^{a; d} | Delatour, Benoît^a | Marty, Serge^{a; *}

Affiliations: [a] Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Hôpital de la Pitié Salpêtrière, APHP, Sorbonne Université, Paris, France | [b] Laboratoire de Neuropathologie Raymond Escourolle, Hôpital de la Pitié Salpêtrière, APHP, Sorbonne Université, Paris, France | [c] Neuro-CEB Neuropathology Network: Plate-Forme de Ressources Biologiques, Bâtiment Roger Baillet, Hôpital de la Pitié-Salpêtrière, Paris, France | [d] Laboratoire de Neurogénétique, EPHE, PSL Research University, Paris, France

Correspondence: [*] Corresponding authors: Serge Marty, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Hôpital de la Pitié Salpêtrière, APHP, Sorbonne Université, Paris, France. Tel.: +33 1 57 27 45 25; E-mail: serge.marty@icm-institute.org and Alexandre Androuin, Université de Paris, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Paris, France. E-mail: alexandre.androuin@inserm.fr.

Note: [1] Present address: Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Université de Paris, Paris, France

Abstract: 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.

Keywords: Alzheimer’s disease, amyloid-β, electron microscopy, lysosome

DOI: 10.3233/JAD-215692

Journal: Journal of Alzheimer's Disease, vol. 87, no. 1, pp. 273-284, 2022