title: Intracellular Aβ pathology and early cognitive impairments in a transgenic rat overexpressing human amyloid precursor protein: a multidimensional study.
abstract: Numerous studies have implicated the abnormal accumulation of intraneuronal amyloid-β (Aβ) as an important contributor to Alzheimer's disease (AD) pathology, capable of triggering neuroinflammation, tau hyperphosphorylation and cognitive deficits. However, the occurrence and pathological relevance of intracellular Aβ remain a matter of controversial debate. In this study, we have used a multidimensional approach including high-magnification and super-resolution microscopy, cerebro-spinal fluid (CSF) mass spectrometry analysis and ELISA to investigate the Aβ pathology and its associated cognitive impairments, in a novel transgenic rat model overexpressing human APP. Our microscopy studies with quantitative co-localization analysis revealed the presence of intraneuronal Aβ in transgenic rats, with an immunological signal that was clearly distinguished from that of the amyloid precursor protein (APP) and its C-terminal fragments (CTFs). The early intraneuronal pathology was accompanied by a significant elevation of soluble Aβ42 peptides that paralleled the presence and progression of early cognitive deficits, several months prior to amyloid plaque deposition. Aβ38, Aβ39, Aβ40 and Aβ42 peptides were detected in the rat CSF by MALDI-MS analysis even at the plaque-free stages; suggesting that a combination of intracellular and soluble extracellular Aβ may be responsible for impairing cognition at early time points. Taken together, our results demonstrate that the intraneuronal development of AD-like amyloid pathology includes a mixture of molecular species (Aβ, APP and CTFs) of which a considerable component is Aβ; and that the early presence of these species within neurons has deleterious effects in the CNS, even before the development of full-blown AD-like pathology.
authors.forename: M Florencia
authors.initials: MF
authors.lastname: Iulita
authors.forename: Simon
authors.initials: S
authors.lastname: Allard
authors.forename: Luise
authors.initials: L
authors.lastname: Richter
authors.forename: Lisa-Marie
authors.initials: LM
authors.lastname: Munter
authors.forename: Adriana
authors.initials: A
authors.lastname: Ducatenzeiler
authors.forename: Christoph
authors.initials: C
authors.lastname: Weise
authors.forename: Sonia
authors.initials: S
authors.lastname: Do Carmo
authors.forename: William L
authors.initials: WL
authors.lastname: Klein
authors.forename: Gerhard
authors.initials: G
authors.lastname: Multhaup
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, 3655 Sir-William-Osler Promenade, Room 1210, Montreal, Quebec, Canada. claudio.cuello@mcgill.ca.
authors.forename: A Claudio
authors.initials: AC
authors.lastname: Cuello
mesh_terms: D000161:Acoustic Stimulation / Q000009:adverse effects; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D003072:Cognition Disorders / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003213:Conditioning, Psychological / Q000502:physiology; D004195:Disease Models, Animal; D005239:Fear; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D010147:Pain Measurement; D010446:Peptide Fragments / Q000378:metabolism*; D051381:Rats; D055647:Rats, Transgenic; D021641:Recognition, Psychology / Q000502:physiology; D012044:Regression Analysis
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases