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Early Endosomal Abnormalities and Cholinergic Neuron Degeneration in Amyloid-β Protein Precursor Transgenic Mice

Article type: Research Article

Authors: Choi, Jennifer H.K.a; c; 1; 2 | Kaur, Gurjindera; 1 | Mazzella, Matthew J.a | Morales-Corraliza, Josea; b | Levy, Efrata; b; d; * | Mathews, Paul M.a; b; *

Affiliations: [a] Nathan S. Kline Institute, Orangeburg, NY, USA | [b] Department of Psychiatry, NYU Langone School of Medicine, New York, NY, USA | [c] Department of Physiology and Neuroscience, NYU Langone School of Medicine, New York, NY, USA | [d] Department of Biochemistry and Molecular Pharmacology, NYU Langone School of Medicine, New York, NY, USA

Correspondence: [*] Correspondence to: Paul M. Mathews and Efrat Levy, Nathan S. Kline Institute, Center for Dementia Research, 140 Old Orangeburg Rd, Bldg 39, Orangeburg, NY 10962, USA. Tel.: +1 845 398 5428; Fax: +1 845 398 5422; E-mail: [email protected] or [email protected].

Note: [1] These authors contributed equally to this work.

Note: [2] Current affiliation: Department of Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Keywords: Alzheimer's disease, amyloid-β protein precursor, cholinergic neurons, endocytosis, endosomes, septal nuclei

DOI: 10.3233/JAD-122143

Journal: Journal of Alzheimer's Disease, vol. 34, no. 3, pp. 691-700, 2013

Accepted 26 November 2012
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Published: 4 March 2013
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Abstract

Early endosomal changes, a prominent pathology in neurons early in Alzheimer's disease, also occur in neurons and peripheral tissues in Down syndrome. While in Down syndrome models increased amyloid-β protein precursor (AβPP) expression is known to be a necessary contributor on the trisomic background to this early endosomal pathology, increased AβPP alone has yet to be shown to be sufficient to drive early endosomal alterations in neurons. Comparing two AβPP transgenic mouse models, one that contains the AβPP Swedish K670N/M671L double mutation at the β-cleavage site (APP23) and one that has the AβPP London V717I mutation near the γ-cleavage site (APPLd2), we show significantly altered early endosome morphology in fronto-parietal neurons as well as enlargement of early endosomes in basal forebrain cholinergic neurons of the medial septal nucleus in the APP23 model, which has the higher levels of AβPP β-C-terminal fragment (βCTF) accumulation. Early endosomal changes correlate with a marked loss of the cholinergic population, which is consistent with the known dependence of the large projection cholinergic cells on endosome-mediated retrograde neurotrophic transport. Our findings support the idea that increased expression of AβPP and AβPP metabolites in neurons is sufficient to drive early endosomal abnormalities in vivo, and that disruption of the endocytic system is likely to contribute to basal forebrain cholinergic vulnerability.

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