ABSTRACT
At diagnosis, Alzheimer's 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 ß (Aß)-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 Aß-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 Aß-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.
Subject(s)
Alzheimer Disease/drug therapy , Alzheimer Disease/genetics , Disease Models, Animal , Age Factors , Alzheimer Disease/complications , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Analysis of Variance , Animals , Cerebellum/metabolism , Cerebral Cortex/metabolism , Cognition Disorders/etiology , Drug Evaluation, Preclinical , Gene Expression Regulation/genetics , Hippocampus/metabolism , Humans , Maze Learning/physiology , Mice , Mice, Transgenic , Mutation/genetics , Nuclear Receptor Subfamily 4, Group A, Member 2/metabolism , Peptide Fragments/metabolism , Phosphopyruvate Hydratase/metabolism , Recognition, Psychology/physiology , Vesicular Acetylcholine Transport Proteins/metabolismABSTRACT
BACKGROUND: Intracellular accumulation of beta-amyloid (Abeta) is one of the early features in the neuropathology of Alzheimer's disease (AD) and Down's syndrome. This can be reproduced in cell and transgenic animal models of the AD-like amyloid pathology. In a transgenic rat model, our lab has previously shown that the intracellular accumulation of Abeta is sufficient to provoke cognitive impairments and biochemical alterations in the cerebral cortex and hippocampus in the absence of amyloid plaques. OBJECTIVE: To investigate an early, pre-plaque inflammatory process in AD-like transgenic models and establish whether the neurotoxic effects of Abeta oligomers and proinflammatory responses can be arrested with minocycline. METHODS: For these studies, we used naïve mice and transgenic animal models of the AD-like amyloid pathology and applied neurochemical, immunohistochemical and behavioral experimental approaches. RESULTS: In the early stages of the AD-like amyloid pathology, intracellular Abeta oligomers accumulate within neurons of the cerebral cortex and hippocampus. Coincidental with this, behavioral impairments occur prior to the appearance of amyloid plaques, together with an upregulation of MHC-II, i-NOS and COX-2, well-known proinflammatory markers. Treatment with minocycline corrected behavioral impairments, lowered inflammatory markers and levels of Abeta trimers. CONCLUSION: A pharmacological approach targeting the early neuroinflammatory effects of Abeta might be a promising strategy to prevent or delay the onset of AD.
