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(Accepted July 29, 2002)
Previous experimental studies have indicated that amyloid-b peptide (Ab) may cause axonal degeneration in the brain of individuals with Alzheimer's disease (AD) by physical injury, mass lesion, or membrane perturbation. In this study, acetylcholinesterase histochemical, and Ab and tau immunohistochemical double-staining were performed in nondemented elderly human hippocampal and entorhinal brain samples, to demonstrate the presence of dystrophic neurites caused by the C-terminal or N-terminal fragments of Ab. The early interactions between the Ab-stained senile plaques (SPs) and the enzyme-positive axons were investigated. The doublestained samples revealed that Ab deposition occurs first, followed by the development of cholinergic axonal damage. Most of the dystrophic axonal processes are incorporated in the peripheral area of the SPs and are positive for phosphorylated tau [pS202] and tau-5. The result suggests that C-terminal fragments are more harmful than N-terminal fragments of Ab and may induce the development of dystrophic neurites by a toxic effect rather than by physical injury.
KEY WORDS: Acetylcholinesterase; aging; amyloid-b; chemical toxicity; dystrophic neurite; physical injury.
INTRODUCTION
Alzheimer's disease (AD) is a progressive neurodegenerative disorder. The brain regions that are most affected include the neocortex, the hippocampus, and the basal forebrain (1). The most characteristic neuropathological changes are the extracellular deposits of amyloid-beta peptide (Ab) in senile plaques (SPs), the formation of neurofibrillary tangles (NFTs) and the loss of various transmitter-containing neurons. In the development of AD, the loss of acetylcholinecontaining neurons may play a significant role (for references see 2). It has also been demonstrated in both in vitro (3) and in vivo (4) experiments that Ab is neurotoxic to various types of neurons. The relationship between the axonal degeneration and the Ab-containing SPs is controversial. It is known that the size, shape, and Ab content of the SPs change over time, dystrophic neuritic processes being involved. Whether the dystrophic axons in the SPs develop in a nontoxic way as a result of physical injury, because of the mass lesion of Ab, or because Ab affects the axonal membranes as a toxic agent is still in question.
Vickers et al. (5) reported that the dystrophic axonal changes in the SPs are associated with physical injury. On the basis of their experiments, they hypothesized that Ab plaque causes physical trauma...