Modulation of Secreted β-Amyloid Precursor Protein and Amyloid β-Peptide in Brain by Cholesterol

Abstract

The effects of dietary cholesterol on brain amyloid precursor protein (APP) processing were examined using an APP gene-targeted mouse, genetically humanized in the amyloid ␤-peptide (A␤) domain and expressing the Swedish familial Alzheimer's disease mutations. These mice express endogenous levels of APP holoprotein and abundant human A␤. Increased dietary cholesterol led to significant reductions in brain levels of secreted APP derivatives, including sAPP␣, sAPP␤, A␤1-40, and A␤1-42, while having little to no effect on cellassociated species, including full-length APP and the COOH-terminal APP processing derivatives. The changes in levels of sAPP and A␤ in brain all were negatively correlated with serum cholesterol levels and levels of serum and brain apoE. These results demonstrate that secreted APP processing derivatives and A␤ can be modulated in the brain of an animal by diet and provide evidence that cholesterol plays a role in the modulation of APP processing in vivo. APP gene-targeted mice lacking apoE, also have high serum cholesterol levels but do not show alterations in APP processing, suggesting that effects of cholesterol on APP processing require the presence of apoE.Alzheimer's disease (AD) 1 pathology includes extracellular amyloid deposits, intracellular neurofibrillary tangles, synaptic loss, and neuronal death (for a review, see Ref. 1). Alterations in the production or processing of APP have been implicated in the etiology of at least some forms of AD (2, 3). Multiple pathways for APP processing have been described, including a nonamyloidogenic pathway in which a putative ␣-secretase cleaves within the A␤ domain (4, 5), resulting in the formation of a secreted NH 2 -terminal fragment, sAPP␣, and a cell-associated 9-kDa COOH-terminal derivative. Another fraction of APP is processed along an amyloidogenic pathway in which cleavage by a putative ␤-secretase at the NH 2 terminus of the A␤ domain results in the formation of a secreted NH 2 -terminal fragment, sAPP␤ (6), and a cell-associated 12-kDa COOH-terminal derivative that may be the immediate precursor of A␤ (7,8). Cleavage of APP by both ␤-secretase and ␥-secretase results in formation of A␤, 40 or 42 amino acids in length (9, 10), that is found deposited in extracellular amyloid plaques in the AD brain (1, 11).In order to elucidate mechanisms of APP processing and A␤ generation in vivo, an animal model was developed by gene targeting that converted the mouse A␤ sequence to human and incorporated the Swedish familial Alzheimer's disease mutations (12). Enhanced amyloidogenic APP processing by the Swedish mutations, resulting in higher level A␤ production has been well documented in cell culture systems (13-15) and in the APP gene-targeted mice (12). These mice are well suited for investigating modulation of APP processing in vivo, because brain A␤ levels are nearly 10-fold above normal endogenous levels, thereby reducing the stringency for assays to detect A␤, particularly for the less abundant but more amyloidogenic 42-residue form. Further...

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

“…76 Thus RAGE plays a direct and indirect role in AD pathogenesis, in particular, the apparent inverse relationship between sRAGE and cholesterol may add yet another modulatory effect on Ab metabolism as cholesterol is a known mediator of inflammation and APP processing. [93][94][95][96][97][98][99][100][101][102][103][104] Efflux of Ab: LRP-1/Ab interactions at BBB LRP-1 is a multi-ligand lipoprotein receptor involved in the mediation of endocytosis or activation of signalling molecules for a diverse range of secreted and membrane-bound ligands. Receptor activating protein (RAP) is a 39 kDa chaperone protein that binds to LRP-1 and regulates its tertiary structure.…”

Plasma lipoprotein β-amyloid in subjects with Alzheimer's disease or mild cognitive impairment

“…In transgenic mice expressing the Swedish familial AD mutations, changes in concentrations of sAPP and Ab in brain were all negatively correlated with serum cholesterol concentrations. 47 ABCA1 promotes cholesterol efflux from cells and is required for maintaining plasma cholesterol concentrations. In a study by Burns et al 18 overexpression of ABCA1 achieved by stimulating liver X receptors increased plasma cholesterol and apo E, commensurate with a decrease in brain Ab.…”

Brain Cholesterol: Long Secret Life Behind a Barrier

“…Numerous studies using immortalized and primary cell lines [83][84][85] have demonstrated that increased cholesterol levels can increase the activity of the ␤-secretase pathway, leading to an accumulation of A␤ and A␤ 1-42 peptides, with a resulting increase in formation of extracellular amyloid deposits. Moreover, it has recently been demonstrated that cholesterol is capable of modulating the production of mature glycosylated APP.…”