Intracellular A beta pathology and early cognitive impairments in a transgenic rat overexpressing human amyloid precursor protein: a multidimensional study

Numerous studies have implicated the abnormal accumulation of intraneuronal amyloid-beta (A beta) 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 A beta 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 A beta 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 A beta 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 A beta(42) peptides that paralleled the presence and progression of early cognitive deficits, several months prior to amyloid plaque deposition. A beta(38), A beta(39), A beta(40) and A beta(42) 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 A beta 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 (A beta, APP and CTFs) of which a considerable component is A beta; 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.