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.Electronic supplementary materialThe online version of this article (doi:10.1186/2051-5960-2-61) contains supplementary material, which is available to authorized users.
Highlights
Alzheimer’s disease (AD) remains the most common form of age-related dementia, a disorder which affects approximately 36 million sufferers worldwide [1]
Progression of the amyloid pathology in McGill-R-Thy1-amyloid precursor protein (APP) transgenic rats This study provides a quantitative biochemical and morphological investigation of the evolution of the Aβ pathology and its associated cognitive impairments in McGill-R-Thy1-APP rats
The expression of Aβ-immunoreactive material is detectable as early as 1 week of age and the first isolated amyloid plaques may appear between 6 – 8 months starting in the subiculum [11]
Summary
Alzheimer’s disease (AD) remains the most common form of age-related dementia, a disorder which affects approximately 36 million sufferers worldwide [1]. Recent studies have revealed the existence of a long asymptomatic phase, where the pathological changes leading to AD begin –at least- decades before the first symptoms of cognitive decline appear [2,3,4]. These studies have addressed the temporal order in which AD pathological hallmarks appear, the exact sequence of cellular and molecular events that lead to AD is still poorly understood. Little is known about this early phase, as most studies of the AD pathology center on moderate-to-late stages. This preclinical period deserves further attention, as it should offer a critical window for successful treatment
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