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Abstract

Alzheimer’s disease (AD) is neuropathologically characterized by the combined occurrence of extracellular β-

amyloid plaques and intracellular neurofibrillary tangles in the brain. While plaques contain aggregated forms of the

amyloid β-peptide (Aβ), tangles are formed by fibrillar forms of the microtubule associated protein tau. All mutations

identified so far to cause familial forms of early onset AD (FAD) are localized close to or within the Aβ domain

of the amyloid precursor protein (APP) or in the presenilin proteins that are essential components of a protease

complex involved in the generation of Aβ. Mutations in the tau gene are not associated with FAD, but can cause

other forms of dementia. The genetics of FAD together with biochemical and cell biological data, led to the formulation

of the amyloid hypothesis, stating that accumulation and aggregation of Aβ is the primary event in the

pathogenesis of AD, while tau might mediate its toxicity and neurodegeneration.

The generation of Aβ involves sequential proteolytic cleavages of the amyloid precursor protein (APP) by enzymes

called β-and γ-secretases. Notably, APP itself as well as the secretases are integral membrane proteins. Thus, it is

very likely that membrane lipids are involved in the regulation of subcellular transport, activity, and metabolism of

AD related proteins.

Indeed, several studies indicate that membrane lipids, including cholesterol and sphingolipids (SLs) affect Aβ

generation and aggregation. Interestingly, APP and other AD associated proteins, including β-and γ-secretases can,

in turn, influence lipid metabolic pathways. Here, we review the close connection of cellular lipid metabolism and

AD associated proteins and discuss potential mechanisms that could contribute to initiation and progression of AD.

Keywords: Alzheimer’s disease, Sphingolipids, Gangliosides, Cholesterol, Tau, Beta-amyloid, Lysosomal storage

disorders

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