Transgenic Mice as a Model of Pre-Clinical Alzheimers Disease

M.      T. Ferretti; V.      Partridge; W.      C. Leon; F.      Canneva; S.      Allard; D.      N. Arvanitis; F.      Vercauteren; D.      Houle; A.      Ducatenzeiler; W.      L. Klein; C.      G. Glabe; M.      Szyf; A.      C. Cuello

Abstract

At diagnosis, Alzheimers disease (AD) brains are extensively burdened with plaques and tangles and display a degree of synaptic failure most likely beyond therapeutic treatment. It is therefore crucial to identify early pathological events in the progression of the disease. While it is not currently feasible to identify and study early, pre-clinical stages of AD, transgenic (Tg) models offer a valuable tool in this regard. Here we investigated cognitive, structural and biochemical CNS alterations occurring in our newly developed McGill-Thyl-APP Tg mice (over-expressing the human amyloid precursor protein with the Swedish and Indiana mutations) prior to extracellular plaque deposition. Pre-plaque, 3-month old Tg mice already displayed cognitive deficits concomitant with reorganization of cortical cholinergic pre-synaptic terminals. Conformational specific antibodies revealed the early appearance of intracellular amyloid β (Aβ)-oligomers and fibrillar oligomers in pyramidal neurons of cerebral cortex and hippocampus. At the same age, the cortical levels of insulin degrading enzyme -a well established Aβ-peptidase, were found to be significantly down-regulated. Our results suggest that, in the McGill-Thy1-APP Tg model, functional, structural and biochemical alterations are already present in the CNS at early, pre-plaque stages of the pathology. Accumulation of intraneuronal neurotoxic Aβ-oligomers (possibly caused by a failure in the clearance machinery) is likely to be the culprit of such early, pre-plaque pathology. Similar neuronal alterations might occur prior to clinical diagnosis in AD, during a yet undefined ‘latent’ stage. A better understanding of such pre-clinical AD might yield novel therapeutic targets and or diagnostic tools.

Keywords: Aβ-oligomers, ADDLs, cholinergic synapse, IDE, neprilysin, pre-clinical Alzheimer's disease, Dementia, Memory loss, Fibrilliar amyloid beta peptide, Western blotting, monoclonal antbody, Morris Water Maze, Dystrophic neurites, hippocampus