Amyloid beta (A ) peptides are known to accumulate in the brain of patients with Alzheimer's disease (AD). However, the link between brain amyloidosis and clinical symptoms has not been elucidated and could be mediated by secondary neuropathological alterations such as fiber tracts anomalies. In the present study, we have investigated the impact of A overproduction in APPxPS1 transgenic mice on the integrity of forebrain axonal bundles (corpus callosum and anterior commissure). We found evidence of fiber tract volume reductions in APPxPS1 mice that were associated with an accelerated age-related loss of axonal neurofilaments and a myelin breakdown. The severity of these defects was neither correlated with the density of amyloid plaques nor associated with cell neurodegeneration. Our data suggest that commissural fiber tract alterations are present in A -overproducing transgenic mice and that intracellular A accumulation preceding extracellular deposits may act as a trigger of such morphological anomalies. 1. Introduction Alzheimer’s disease (AD) is a highly prevalent neurodegenerative disease accompanied by gradual and irreversible behavioral and cognitive impairments. Brain lesions observed during the course of AD involve two main aspects: extr-acellular amyloid-beta (Aβ) deposition in the senile plaques and intracellular tau accumulation forming neurofibrillary tangles and promoting cytoskeletal disorganization. Current research on AD is largely guided by a dominant pathogenic theory, the so-called amyloid cascade hypothesis [1]. Regularly commented on and amended [2], this model posits accumulation of Aβ in the brain as a key primary event that determines the onset of other brain alterations (e.g., synaptic and neuronal death), finally leading to the dementia. Early onset familial forms of AD are indeed associated with mutations in different genes (amyloid precursor protein (APP) and presenilins 1&2, (PS1&2)) involved in the biosynthesis of Aβ. Dysfunction of these genes is logically thought to alter the rate of APP cleavage, resulting in exaggerated Aβ production. High levels of brain Aβ and associated parenchymal amyloid plaques are key phenotypes described in transgenic mice overexpressing one or more of these mutated genes (see [3] for review). These mice subsequently develop neuropathological alterations and behavioral impairments mimicking AD phenotype [4, 5]. The exact impact of brain Aβ accumulation on clinical symptoms remains to date difficult to decipher, both in AD patients and in animal models of the disease. Clinicopathological
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