The Molecular Bases of Alzheimer's Disease and Other Neurodegenerative Disorders

Abstract

Alzheimer's disease, the cause of one of the most common types of dementia, is a brain disorder affecting the elderly and is characterized by the formation of two main protein aggregates: senile plaques and neurofibrillary tangles, which are involved in the process leading to progressive neuronal degeneration and death. Neurodegeneration in Alzheimer's disease is a pathologic condition of cells rather than an accelerated way of aging. The senile plaques are generated by a deposition in the human brain of fibrils of the β-amyloid peptide (Aβ), a fragment derived from the proteolytic processing of the amyloid precursor protein (APP). Tau protein is the major component of paired helical filaments (PHFs), which form a compact filamentous network described as neurofibrillary tangles (NFTs). Experiments with hippocampal cells in culture have indicated a relationship between fibrillary amyloid and the cascade of molecular signals that trigger tau hyperphosphorylations. Two main protein kinases have been shown to be involved in anomalous tau phosphorylations: the cyclin-dependent kinase Cdk5 and glycogen synthase kinase GSK3β. Cdk5 plays a critical role in brain development and is associated with neurogenesis as revealed by studies in brain cells in culture and neuroblastoma cells. Deregulation of this protein kinase as induced by extracellular amyloid loading results in tau hyperphosphorylations, thus triggering a sequence of molecular events that lead to neuronal degeneration. Inhibitors of Cdk5 and GSK3β and antisense oligonucleotides exert protection against neuronal death. On the other hand, there is cumulative evidence from studies in cultured brain cells and on brains that oxidative stress constitutes a main factor in the modification of normal signaling pathways in neuronal cells, leading to biochemical and structural abnormalities and neurodegeneration as related to the pathogenesis of Alzheimer's disease. This review is focused on the main protein aggregates responsible for neuronal death in both sporadic and familial forms of Alzheimer's disease, as well as on the alterations in the normal signaling pathways of functional neurons directly involved in neurodegeneration. The analysis is extended to the action of neuroprotective factors including selective inhibitors of tau phosphorylating protein kinases, estrogens, and antioxidants among other molecules that apparently prevent neuronal degeneration.

Introduction

In 1911, Alois Alzheimer described a neuropsychiatric disorder affecting the elderly, which is widely known today as Alzheimer's disease (AD). Early studies of patients afflicted with this disease demonstrated, via silver staining, the presence of lesions in the brain cortex. Those lesions corresponded to neurofibrillary tangles (NFTs), which are histopathologic structures localized within the neuronal cells. A molecular genetic and histologic analysis of the neuropsychiatric case described by Alzheimer has been reported (1). In 1930, Divry succeeded in staining another pathologic structure, the senile plaques using the dye Congo Red, which bound to a component called amyloid on the basis of its physicochemical properties resembling those of polysaccharides. Senile plaques formed by deposits of amyloid fibrils were localized extracellularly in the brain. The intraneuronal aggregates (NFTs) were shown by Kidd and co-workers at the electron microscopic level to be formed by paired helical filaments (PHFs), thin filaments of 10 nm in diameter (2). It was not until the middle of the 1980s that the core protein component of PHFs was identified as the microtubule-associated protein tau by the groups of Wisniewski in the U.S. and Brion in Belgium 3, 4, 5. Close to the same time, Glenner and collaborators found that the amyloid deposits were composed of a 4-kDa peptide with a significant beta structure called beta amyloid (Aβ). The Aβ peptide is derived from the proteolysis of the amyloid precursor protein APP (6). This background of previous findings was the basis for the impressive progress attained during the Brain Decade of the 1990s in the knowledge of the molecular and genetic basis of Alzheimer's disease. This cumulus of information contributed enormously to clarify the pathogenesis of AD and provides the basis for taking further steps toward an effective therapy for AD and related neurodegenerative disorders (for reviews see References 7 and 8).

The majority of cases of AD correspond to the sporadic form of this disorder. Approximately 5–10% of patients present an autosomal mode of transmission and account for cases called familial Alzheimer's disease (FAD) 8, 9, 10. Therefore, elucidation of the factors that trigger the sequence of changes in the normal neuronal machinery leading to neurodegeneration and the mechanisms underlying signal transductions that determine neuronal death in AD brains is of utmost importance. Knowledge of the detailed molecular aspects and the involvement of specified genes and several other risk factors (11) have shed light on the etiology of AD and has also contributed to the understanding of the pathologic basis of the more frequent sporadic form of this ailment.