title: Presynaptic dystrophic neurites surrounding amyloid plaques are sites of microtubule disruption, BACE1 elevation, and increased Aβ generation in Alzheimer's disease.
abstract: Alzheimer's disease (AD) is characterized by amyloid plaques composed of the β-amyloid (Aβ) peptide surrounded by swollen presynaptic dystrophic neurites consisting of dysfunctional axons and terminals that accumulate the β-site amyloid precursor protein (APP) cleaving enzyme (BACE1) required for Aβ generation. The cellular and molecular mechanisms that govern presynaptic dystrophic neurite formation are unclear, and elucidating these processes may lead to novel AD therapeutic strategies. Previous studies suggest Aβ may disrupt microtubules, which we hypothesize have a critical role in the development of presynaptic dystrophies. To investigate this further, here we have assessed the effects of Aβ, particularly neurotoxic Aβ42, on microtubules during the formation of presynaptic dystrophic neurites in vitro and in vivo. Live-cell imaging of primary neurons revealed that exposure to Aβ42 oligomers caused varicose and beaded neurites with extensive microtubule disruption, and inhibited anterograde and retrograde trafficking. In brain sections from AD patients and the 5XFAD transgenic mouse model of amyloid pathology, dystrophic neurite halos with BACE1 elevation around amyloid plaques exhibited aberrant tubulin accumulations or voids. At the ultrastructural level, peri-plaque dystrophies were strikingly devoid of microtubules and replete with multi-lamellar vesicles resembling autophagic intermediates. Proteins of the microtubule motors, kinesin and dynein, and other neuronal proteins were aberrantly localized in peri-plaque dystrophies. Inactive pro-cathepsin D also accumulated in peri-plaque dystrophies, indicating reduced lysosomal function. Most importantly, BACE1 accumulation in peri-plaque dystrophies caused increased BACE1 cleavage of APP and Aβ generation. Our study supports the hypothesis that Aβ induces microtubule disruption in presynaptic dystrophic neurites that surround plaques, thus impairing axonal transport and leading to accumulation of BACE1 and exacerbation of amyloid pathology in AD.
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Sadleir
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
authors.forename: Patty C
authors.initials: PC
authors.lastname: Kandalepas
authors.affiliation: Departments of Neurobiology, Neurology and Pathology, The University of Chicago, Chicago, IL, 60637, USA.|The Neurodegeneration Consortium, Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA.
authors.forename: Virginie
authors.initials: V
authors.lastname: Buggia-Prévot
authors.affiliation: Department of Neurological Sciences, Rush University, Chicago, IL, 60612, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Nicholson
authors.affiliation: Departments of Neurobiology, Neurology and Pathology, The University of Chicago, Chicago, IL, 60637, USA.
authors.forename: Gopal
authors.initials: G
authors.lastname: Thinakaran
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. r-vassar@northwestern.edu.
authors.forename: Robert
authors.initials: R
authors.lastname: Vassar
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D001369:Axons / Q000473:pathology; D004195:Disease Models, Animal; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016501:Neurites / Q000473:pathology*; D058225:Plaque, Amyloid / Q000473:pathology; D017729:Presynaptic Terminals / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
keywords: 5XFAD mice; Alzheimer’s disease; Amyloid; Axonal transport; Aβ; BACE1; Cathepsin D; Dystrophic neurite; Microtubule; Tubulin