A Partial Failure of Membrane Protein Turnover May Cause Alzheimers Disease: A New Hypothesis

Abstract

The amyloid hypothesis has dominated the thinking in our attempts to understand, diagnose and develop drugs for Alzheimer's disease (AD). This article presents a new hypothesis that takes into account the numerous familial AD (FAD) mutations in the amyloid precursor protein (APP) and its processing pathways, but suggests a new perspective beyond toxicity of forms of the amyloid beta-peptide (Abeta). Clearly, amyloid deposits are an invariable feature of AD. Moreover, although APP is normally processed to secreted and membrane-bound fragments, sAPPbeta and CTFbeta, by BACE, and the latter is subsequently processed by gamma-secretase to Abeta and CTFgamma, this pathway mostly yields Abeta of 40 residues, and increases in the levels of the amyloidogenic 42-residue Abeta (Abeta42) are seen in the majority of the mutations linked to the disease. The resulting theory is that the disease is caused by amyloid toxicity, which impairs memory and triggers deposition of the microtubule associated protein, Tau, as neurofibrillary tangles. Nevertheless, a few exceptional FAD mutations and the presence of large amounts of amyloid deposits in a group of cognitively normal elderly patients suggest that the disease process is more complex. Indeed, it has been hard to demonstrate the toxicity of Abeta42 and the actual target has been shifted to small oligomers of the peptide, named Abeta derived diffusible ligands (ADDLs). Our hypothesis is that the disease is more complex and caused by a failure of APP metabolism or clearance, which simultaneously affects several other membrane proteins. Thus, a traffic jam is created by failure of important pathways such as gamma-secretase processing of residual intramembrane domains released from the metabolism of multiple membrane proteins, which ultimately leads to a multiple system failure. In this theory, toxicity of Abeta42 will only contribute partially, if at all, to neurodegeneration in AD. More significantly, this theory would predict that focussing on specific reagents such as gamma-secretase inhibitors that hamper metabolism of APP, may initially show some beneficial effects on cognitive performance by elimination of acutely toxic ADDLs, but over the longer term may exacerbate the disease process by reducing membrane protein turnover.

Pigment Epithelium-derived Factor Maintains Retinal Pigment Epithelium Function by Inhibiting Vascular Endothelial Growth Factor-R2 Signaling through γ-Secretase

“…The protein is responsible for the final step in processing APP into A␤ (34), aggregated forms of which accumulate in Alzheimer disease. Functionally, ␥-secretase is an endopeptidase, which can digest the membranespanning region of any type-1 integral membrane protein, after the ectodomain has been removed (35,36). Thus, ␥-secretase is seen as the "proteasome" of cell membranes (37,38).…”

Loss of γ-Secretase Function Impairs Endocytosis of Lipoprotein Particles and Membrane Cholesterol Homeostasis

“…Although AICD could affect gene transcription by association with Fe65 in vitro, its release from cellular membranes by ␥-secretase appears to be not absolutely required (Biederer et al, 2002;Cao and Sudhof, 2004;Hass and Yankner, 2005). Thus, the ␥-secretase-dependent cleavage of APP CTFs and probably other substrates might not be important for nuclear signaling, but rather serve for degradation of certain membrane proteins (Kopan and Ilagan, 2004;Sambamurti et al, 2006;Selkoe and Wolfe, 2007). Accumulation of other ␥-secretase substrates might therefore also contribute to the pathogenesis of AD.…”

Isolation of 6,6'-Bieckol from Grateloupia elliptica and its Antioxidative and Anti-Cholinesterase Activity

“…The neurodegenerative features of AD include classical pathological changes in the brain, such as the formation of β-amyloid plaques, neurofibrillary tangles, neuronal cell death and a dramatic synaptic loss (Selkoe 2005;Sambamurti et al 2002). However, the initiating factors that underpin this pathology remain to be elucidated (Sambamurti et al 2006). In particular, AD is associated with early substantial reductions in presynaptic markers of the cholinergic system.…”