title: Transgenic expression of intraneuronal Aβ42 but not Aβ40 leads to cellular Aβ lesions, degeneration, and functional impairment without typical Alzheimer's disease pathology.
abstract: An early role of amyloid-β peptide (Aβ) aggregation in Alzheimer's disease pathogenesis is well established. However, the contribution of intracellular or extracellular forms of Aβ to the neurodegenerative process is a subject of considerable debate. We here describe transgenic mice expressing Aβ1-40 (APP47) and Aβ1-42 (APP48) with a cleaved signal sequence to insert both peptides during synthesis into the endoplasmic reticulum. Although lower in transgene mRNA, APP48 mice reach a higher brain Aβ concentration. The reduced solubility and increased aggregation of Aβ1-42 may impair its degradation. APP48 mice develop intracellular Aβ lesions in dendrites and lysosomes. The hippocampal neuron number is reduced already at young age. The brain weight decreases during aging in conjunction with severe white matter atrophy. The mice show a motor impairment. Only very few Aβ1-40 lesions are found in APP47 mice. Neither APP47 nor APP48 nor the bigenic mice develop extracellular amyloid plaques. While intracellular membrane expression of Aβ1-42 in APP48 mice does not lead to the AD-typical lesions, Aβ aggregates develop within cells accompanied by considerable neurodegeneration.
authors.affiliation: Novartis Institutes for Biomedical Research, CH-4056 Basel, Switzerland.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Abramowski
authors.forename: Sabine
authors.initials: S
authors.lastname: Rabe
authors.forename: Ajeet Rijal
authors.initials: AR
authors.lastname: Upadhaya
authors.forename: Julia
authors.initials: J
authors.lastname: Reichwald
authors.forename: Simone
authors.initials: S
authors.lastname: Danner
authors.forename: Dieter
authors.initials: D
authors.lastname: Staab
authors.forename: Estibaliz
authors.initials: E
authors.lastname: Capetillo-Zarate
authors.forename: Haruyasu
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Takaomi C
authors.initials: TC
authors.lastname: Saido
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Wiederhold
authors.forename: Dietmar Rudolf
authors.initials: DR
authors.lastname: Thal
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000235:genetics*; D000818:Animals; D005786:Gene Expression Regulation; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000235:genetics*; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)