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Review
. 2002;2(2):151-65.
doi: 10.1385/NMM:2:2:151.

Axonal transport, tau protein, and neurodegeneration in Alzheimer's disease

Dick Terwel  1 , Ilse Dewachter, Fred Van Leuven
Affiliations
Review

Axonal transport, tau protein, and neurodegeneration in Alzheimer's disease

Dick Terwel et al. Neuromolecular Med. 2002.

Abstract

The molecular causes and the genetic and environmental modifying factors of the sporadic form of Alzheimer's disease (AD) remain elusive. Extrapolating from the known mutations that cause the rare familial forms and from the typical post-mortem pathological lesions in all AD patients--e.g., amyloid plaques and neurofibrillary tangles (NFTs)-the evident molecular candidates are amyloid precursor protein (APP), presenilin, and tau protein. To include ApoE4 as the only certain genetic modifier known leaves us to face the challenge of implementing these very different molecules into an evident pathological partnership. In more than one respect, the proposition of disturbed axonal transport appears attractive with more details becoming available on APP processing and microtubular transport and also of the pathology in the model systems--e.g., transgenic mice expressing APP or protein tau. Conversely, the resistance of APP-transgenic mice with full-blown amyloid pathology to also develop tau-related neurofibrillar pathology is a major challenge for this hypothesis. From the most relevant data discussed here, we conclude that the postulate of disturbed axonal transport as the primary event in AD is difficult to defend. On the other hand, failing axonal transport appears to be of major importance in the later stages in AD, by further compromising tau protein, APP metabolism, and synaptic functioning. Protein tau may thus be the central "executer" in the chain of events leading from amyloid neurotoxicity to tau hyperphosphorylation, microtubular destabilization, disturbed axonal transport, and synaptic failure to neurodegeneration. In order to identify normal physiological processes and novel pathological targets, definition is needed--in molecular detail--of the complex mechanisms involved.

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