Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewIntracellular cholesterol homeostasis and amyloid precursor protein processing
Introduction
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized histologically by the presence of amyloid plaques and neurofibrillary tangles in the brain. The plaques consist of aggregated proteinaceous material, a major component of which is β-amyloid (Aβ). The neurofibrillary tangles are composed of paired helical filaments of the microtubule associated phosphoprotein, tau. For more than a decade, research has focused on how Aβ is generated, how it impacts cellular function, and how it promotes the pathobiology of tau.
The amyloid precursor protein (APP), located on chromosome 21, was implicated as being a critical player in AD as the Aβ peptide that is found in amyloid plaques is derived from APP following a number of cleavage events, and Down syndrome patients, who have three copies of chromosome 21, always develop AD. In 1991, the first mutations that cause familial forms of AD were identified in APP (reviewed in [1]). In 1995, a second genetic locus, presenilin 1 (PS-1) was found to be associated with familial AD. This was soon followed by the identification of mutations in the presenilin 2 (PS-2) gene. Mutations in APP and the presenilins have as their unifying feature the ability to alter the processing of APP such that more Aβ peptides are produced (reviewed in [1]). It is therefore thought that the accumulation and/or aggregation of Aβ underlies the etiology of the disease, and that preventing this accumulation is a valid therapeutic target. Multiple studies have indicated a role for cholesterol in maintaining normal levels of Aβ in vitro and in vivo. In this review we will discuss the movement of intracellular cholesterol and how normal distribution, transport, and export of cholesterol are vital for homeostatic regulation of Aβ. The major stages of intracellular cholesterol transport are shown in Fig. 1.
Section snippets
Evidence for a role of cholesterol in Alzheimer's disease
Sporadic, late onset AD accounts for greater than 95% of all AD cases [2]. Within these sporadic cases, by far the greatest genetic risk factor is possession of the apolipoprotein E ε4 (APOE4) allele [3], [4]. Not only does APOE genotype act as a risk factor for developing the disease, but also the age of onset of the disease. In an almost dose-respondent manner, the average age of onset for patients with 2 ε4 alleles is less than 70 years of age, with 1 ε4 allele, 80 years, whereas for those
Plasma membrane
Cholesterol has many functions in animal cells, including a vital role in the plasma membrane. Lipids account for approximately 40% of the dry weight of plasma membranes, the remainder consisting of proteins. Phospholipids are the most abundant of these lipids (∼ 70%) with cholesterol being the majority of the remainder (∼ 21%). These proteins and lipids are arranged into bilayer leaflets, which display extraordinary fluidity. One of the major factors influencing this property is the cholesterol
Intracellular cholesterol transport — the endosomal–lysosomal–ER pathway
The endosomal–lysosomal pathway is involved in the proteolytic processing of APP to Aβ [53], [54], [55], [56], [57], [58]. Endosomal abnormalities have been found in AD, where they precede amyloid and tau pathology in the neocortex. Enlarged neuronal endosomes have also been recorded in Down's syndrome (Trisomy 16) prior to dementia symptoms [59], and are thought to be caused by the excess production of APP β-CTF [60]. Thus, factors affecting APP trafficking in endosomal compartments are
Cholesterol at the ER and Golgi
Cholesterol that enters the cell via the endocytic pathway is transported to the endoplasmic reticulum (ER) for processing. The ER is a cholesterol-poor environment where regulation of the cells cholesterol balance is maintained. Within the ER resides the sterol regulatory element binding protein (SREBP). Under cholesterol-poor conditions, SREBP interacts with SREBP cleavage activating protein (Scap). It binds to CopII proteins, which cluster the Scap/SREBP complex into vesicles for transport
The cholesterol biosynthetic pathway
Following cleavage of SREBP in the Golgi, the N-terminus is released and acts as a transcription factor, entering the nucleus and inducing mRNA for HMG-CoA reductase and low density lipoprotein (LDL) receptors. The LDL receptors will allow more exogenous cholesterol to enter the cell, and HMG-CoA reductase production will induce more intracellular cholesterol production.
The cholesterol biosynthetic pathway has five major stages (Fig. 2). Acetyl-CoA is converted to HMG-CoA and mevalonate.
Cholesterol efflux
Once cholesterol has been synthesized at the ER, it is transported to the plasma membrane within a short time frame (half-life of ∼ 10 min) [81]. Cholesterol within the membrane is redistributed throughout the cell, with any excess removed by efflux to extracellular acceptors. The major energy dependent mechanism for cholesterol efflux is via sterol ATP binding cassette (ABC) transporters on the cell surface. There are a number of ABC transporters known to be important for cholesterol efflux
Conclusions
The importance of cellular cholesterol in APP processing relies not simply on the levels of cholesterol in the cell, but also on the distribution of cholesterol in the cell. This distribution can be affected by disease processes (e.g., Down syndrome or Niemann Pick Type C disease), by drug treatments (statins, ACAT inhibitors), or by normal aging. Although an understanding of the normal distribution of cholesterol in the CNS is still just underway, we also need to appreciate the changes that
Acknowledgements
This work was supported by NIH (R01 AG014473 to GWR) and a Wright Family funded award from the Memory Disorder's Program at Georgetown University (MPB).
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