Is Amyloid Binding Alcohol Dehydrogenase a Drug Target for Treating Alzheimer’s Disease?

Abstract

Current strategies for the treatment of Alzheimer's disease (AD) involve tackling the formation or clearance of the amyloid-beta peptide (Aβ) and/or hyper-phosphorylated tau, or the support and stabilization of the remaining neuronal networks. However, as we gain a clearer idea of the large number of molecular mechanisms at work in this disease, it is becoming clearer that the treatment of AD should take a combined approach of dealing with several aspects of the pathology. The concept that we also need to protect specific sensitive targets within the cell should also be considered. In particular the role of protecting the function of a specific mitochondrial protein, amyloid binding alcohol dehydrogenase (ABAD), will be the focus of this review. Mitochondrial dysfunction is a well-recognized fact in the progression of AD, though until recently the mechanisms involved could only be loosely labeled as changes in `metabolism'. The discovery that Aβ can be present within the mitochondria and specifically bind to ABAD, has opened up a new area of AD research. Here we review the evidence that the prevention of Aβ binding to ABAD is a drug target for the treatment of AD.

Alzheimer’s Pathogenesis and Its Link to the Mitochondrion

“…Oxidative stress may facilitate the expression of a protein involved in the generation of A β and the beta-secretase (BACE 1) [ 68 ] and, moreover, may induces a pathogenic PS1 conformational change in neurons, increasing A β 42/40 ratio, as shown by in vitro models [ 69 ]. β -amyloid protein (A β ) interacts with the binding alcohol dehydrogenase protein (ABAD), a mitochondrial-matrix protein, causing mitochondrial oxidative damage and deficiency of the respiratory complexes [ 70 , 71 ]. In view of the fact that A β is not produced locally in the mitochondrion [ 67 ], Hansson Petersen and coworkers investigated the mechanisms by which A β is taken up by mitochondria [ 72 ].…”

Auto-inhibitory Mechanism of the Human Mitochondrial RNase P Protein Complex

“…MRPP2 is a multifunctional protein that is a member of the short-chain dehydrogenase family 21 22 ; however, its dehydrogenase activity is not couple with its role in the endonuclease 20 . Additionally, MRPP2 binds to amyloid-β with high affinity, suggesting potential involvement in the pathogenesis of Alzheimer's disease 23 . The functional role of MRPP2 in the MRPP123 complex has remained unknown until now.…”

Proteomic Analysis of Lymphoblastoid Cells from Nasu-Hakola Patients: A Step Forward in Our Understanding of This Neurodegenerative Disorder

“…The amount of alcohol dehydrogenase (spot 11 in figure 3 ) was 1,1-fold higher in He and under-expressed in Ho (about 2.3-fold change compared to control). Numerous data in the literature [53] – [55] indicate that the interaction between amyloid-beta (Aβ) peptide-binding alcohol dehydrogenase (ABAD) and Aβ is an important mechanism involved in Aβ-mediated mitochondrial and neuronal perturbation. Inhibition of this interaction, in fact, was shown to significantly reduce mitochondrial Aβ accumulation [56] .…”