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New familial forms of cerebral amyloid and dementia

Molecular Psychiatry volume 5, pages 575–576 (2000)Cite this article

Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder that causes a chronically progressive decline in cognitive functions. AD involves neuronal degeneration with impaired cholinergic transmission in the cerebral cortex and hippocampus in areas of the brain particularly associated with memory and higher intellectual functioning. Because of the increase in longevity of populations around the world, AD is a medical problem of escalating social and economic impact. For example, in the United States there are approximately five million elderly individuals with AD and it is estimated that more than 22 million individuals worldwide will have Alzheimer's by 2025.1, 2 The brains of patients suffering from AD are characterized by the progressive deposition of amyloid β (Aβ) protein in plaques and cerebral blood vessels, by the appearance of intraneuronal neurofibrillary tangles (NFT), cell death, and reactive gliosis. NFTs are intraneuronal lesions consisting of 10-nm thick paired helical filaments composed of hyperphosphorylated microtubule-binding protein tau. The amyloid plaques are deposits of Aβ peptides organized in 7–10 nm thick fibrils. Mature plaques contain in addition degenerating axons and dendrites, and are surrounded and invaded by variable numbers of microglia and reactive astrocytes, indicating the presence of an inflammatory component in the neurodegenerative process.3 The pathogenesis of AD is still not completely understood, although mutations in the amyloid precursor protein (APP) on chromosome 21 or presenilins (PS) 1 (chromosome 14) and 2 (chromosome 1) genes have been linked to autosomal dominant forms of familial AD (FAD).4 The inheritance of the apolipoprotein E (apoE, chromosome 19) epsilon4 allele is a prevailing risk factor for AD.5

Amyloid β is generated from the proteolytic cleavage of the APP by two enzymes, called β-secretase and γ-secretase. Recently, both secretases have been identified, providing new molecular targets for those seeking drugs to treat Alzheimer's disease.6, 7 Some APP and PS mutants related to AD increase the proteolytic processing of APP with increasing production of Aβ.8 This indicates that the generation of Aβ appears to be the central event in the pathogenesis of FAD and probably also in the more common sporadic form of AD. ApoE also plays an important role in fibrillogenesis, since the lack of apoE dramatically reduces amyloid deposits in the brain in transgenic mouse models of Alzheimer's disease.9

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Acknowledgements

This work was supported by NIH grants AG08721, AG05891, and AR02594.

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  1. Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, 10016, NY, USA

    R Vidal, J Ghiso & B Frangione

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Correspondence to R Vidal.

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Vidal, R., Ghiso, J. & Frangione, B. New familial forms of cerebral amyloid and dementia. Mol Psychiatry 5, 575–576 (2000). https://doi.org/10.1038/sj.mp.4000797

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