The neuronal cytoskeleton is a complex structure responsive to both intrinsic and extrinsic factors. Defined populations of neurons in the brains of patients with Alzheimer and several other neurodegenerative diseases contain abnormal filamentous accumulations which share elements with the cytoskeleton. Although there is a general consensus that these abnormal filaments do contain cytoskeletal elements, much debate remains regarding which cytoskeletal elements are incorporated and whether the cytoskeletal rearrangement is primary or secondary to other cellular changes. In this book these questions are addressed in a historical perspect ive in light of new data that allows the reinterpretation of previously reported results. Contributions are based on many of the major tech niques of modern biology including biochemistry, molecular biology, electron microscopy and immunocytochemistry. In the view of the editor, this volume is being written at a time when our understanding of the cytopathology of Alzheimer disease is moving from predominantly descriptive to both analytical and mechanistic. I hope that this contribution will provide impetus to speed this transi tion. George Perry Cleveland, Ohio vii ACKNOWLEDGEMENT The support of the Fidia Pharmaceutic Corporation for the computer generated color figure on page 65 is gratefully acknowledged.

Epidemiological studies, modern clinical, neuroimaging, neuropsychological, molecular biological, and genetic studies have considerably enhanced our knowledge about ageing processes of the human brain, its sequelae, diagnostic, and therapeutic possibilities and limits. In addition to Alzheimer's disease and other degenerative dementias, the impact of cerebrovascular lesions and their risk factors in the pathogenesis of cognitive disorders of the aged are increasingly acknowledged, and the recognition of mild cognitive impairment as a frequent initial stage of developing dementia is becoming an increasingly important diagnostic and therapeutic problem. The included papers were presented at the 7th International Symposium in Graz, Sept. 2001 and give a timely overview of the current and future concepts of pathogenesis, diagnosis, and treatment strategies of pathological brain ageing and dementias, early recognition of mild cognitive impairment and future possiblities of prevention of dementing processes.

This book discusses the primary functions of microtubule-associated proteins (MAPs) such as MAP2 and tau in neuronal morphogenesis, as well as relationships between neuronal differentiation and the expression of neuronal intermediate filaments (nestin, alpha internexin, and neurofilament triplet proteins). It emphasizes the importance of several cytoskeletal proteins for neuronal differentiation and morphogenesis, organelle transport, and synaptic functions. The book considers the involvement of tau MAPs in the formation of paired helical filaments in Alzheimer's disease, and it examines the mechanisms of organelle transports and molecular motors such as kinesin, braindynein, and kinesin superfamily proteins. Cytoskeletal proteins involved in synaptic formation and transmitter release and new synaptic junctional-associated proteins are explored as well.

This volume gives an overview of the present state of art on the classification, neuropathology, clinical presentation, neuropsychology, diagnosis, neuroimaging and therapeutic possibilities in non-Alzheimer’s dementias, an increasingly important group of CNS diseases, which account for 7 to 30% of dementing disorders in adults and aged subjects, and thus, represent the second most frequent cause of dementia after Alzheimer’s disease. The monograph provides the newest information for neurologists, psychiatrists, dementia research workers, dementia clinicians, neuropathologists, neurobiologists, and practicing physicians.

Neurofibrillary tangles (NFTs) composed of intracellular aggregates of tau protein are a key neuropathological feature of Alzheimer’s Disease (AD) and other neurodegenerative diseases, collectively termed tauopathies. The abundance of NFTs has been reported to correlate positively with the severity of cognitive impairment in AD. However, accumulating evidences derived from studies of experimental models have identified that NFTs themselves may not be neurotoxic. Now, many of tau researchers are seeking a “toxic” form of tau protein. Moreover, it was suggested that a “toxic” tau was capable to seed aggregation of native tau protein and to propagate in a prion-like manner. However, the exact neurotoxic tau species remain unclear. Because mature tangles seem to be non-toxic component, “tau oligomers” as the candidate of “toxic” tau have been investigated for more than one decade. In this topic, we will discuss our consensus of “tau oligomers” because the term of “tau oligomers” [e.g. dimer (disulfide bond-dependent or independent), multimer (more than dimer), granular (definition by EM or AFM) and maybe small filamentous aggregates] has been used by each researchers definition. From a biochemical point of view, tau protein has several unique characteristics such as natively unfolded conformation, thermo-stability, acid-stability, and capability of post-translational modifications. Although tau protein research has been continued for a long time, we are still missing the mechanisms of NFT formation. It is unclear how the conversion is occurred from natively unfolded protein to abnormally mis-folded protein. It remains unknown how tau protein can be formed filaments [e.g. paired helical filament (PHF), straight filament and twisted filament] in cells albeit in vitro studies confirmed tau self-assembly by several inducing factors. Researchers are still debating whether tau oligomerization is primary event rather than tau phosphorylation in the tau pathogenesis. Inhibition of either tau phosphorylation or aggregation has been investigated for the prevention of tauopathies, however, it will make an irrelevant result if we don’t know an exact target of neurotoxicity. It is a time to have a consensus of definition, terminology and methodology for the identification of “tau oligomers”.

There is now considerable genetic evidence that the type 4 allele of the apolipoprotein E gene is a major susceptibility factor associated with late-onset Alzheimer's disease, the common form of the disease defined as starting after sixty years of age. The role of apolipoprotein E in normal brain metabolism and in the pathogenesis of Alzheimer's disease are new and exciting avenues of research. This book, written by the most outstanding scientists in this new filed, is the first presentation of results concerning the implications of apolipoprotein E on the genetics, cell biology, neuropathology, biochemistry, and therapeutic management of Alzheimer's disease.

As human longevity continues to be extended, so will the impact of age-associated dementia on individual lives and society. Alzheimer’s disease as the most common cause of dementia in the elderly remains a sentinal problem and its underlying pathology is still poorly understood. Available therapeutic strategies require considerable refinement and the development of new therapeutic strategies need input from basic research. Thus continued efforts are necessary both to understand basic mechanisms of the condition and to achieve more powerfull therapies. This volume brings together the reports of basic scientists and clinical investigators. The chapters provide a spectrum of information valuable for clinicians and scientists. This issue bridges the gap between laboratory work in basic science and the development of urgently needed therapeutic strategies. Areas presented are the molecular and cellular biology of the disease, pathogenetic mechanisms and potential therapeutic targets, genetics, risk factors, strategies of prevention and treatment as well as practical aspects of medical and social care for patients with Alzheimer’s disease.