Mitochondrial β-amyloid in Alzheimer's disease

Abstract

It is well established that the intracellular accumulation of Aβ (amyloid β-peptide) is associated with AD (Alzheimer's disease) and that this accumulation is toxic to neurons. The precise mechanism by which this toxicity occurs is not well understood; however, identifying the causes of this toxicity is an essential step towards developing treatments for AD. One intracellular location where the accumulation of Aβ can have a major effect is within mitochondria, where mitochondrial proteins have been identified that act as binding sites for Aβ, and when binding occurs, a toxic response results. At one of these identified sites, an enzyme known as ABAD (amyloid-binding alcohol dehydrogenase), we have identified changes in gene expression in the brain cortex, following Aβ accumulation within mitochondria. Specifically, we have identified two proteins that are up-regulated not only in the brains of transgenic animal models of AD but also in those of human sufferers. The increased expression of these proteins demonstrates the complex and counteracting pathways that are activated in AD. Previous studies have identified approximate contact sites between ABAD and Aβ; on basis of these observations, we have shown that by using a modified peptide approach it is possible to reverse the expression of these two proteins in living transgenic animals and also to recover mitochondrial and behavioural deficits. This indicates that the ABAD-Aβ interaction is potentially an interesting target for therapeutic intervention. To explore this further we used a fluorescing substrate mimic to measure the activity of ABAD within living cells, and in addition we have identified chemical fragments that bind to ABAD, using a thermal shift assay.

Morphology‐Specific Inhibition of β‐Amyloid Aggregates by 17β‐Hydroxysteroid Dehydrogenase Type 10

“…[22] In transgenic mouse models for AD and in human AD sufferers, 17-HSD10 has been shown to have increased expression levels and has gained considerable attention as a result of its ability to bind A, suppress A-induced apoptosis and free-radical generation in neurons. [11] It is known that the interaction between 17-HSD10 and A , A and A (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) takes place in the nanomolar range (K d ~ 40-80 nM), [11] which agrees well with the low cellular concentrations of A peptide expected at the early stages of AD. In addition, mutagenesis and inhibition studies have suggested that the L D loop of 17-HSD10, comprising residues C91-D119, plays a critical role in A binding.…”

“…However, a lack of -sheet structure at acidic pH cannot exclusively account for the observed lack of aggregation inhibition, as it has been shown that 17-HSD10 does not bind A (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), which is known to exhibit a -sheet conformation by CD and NMR studies. [63] In contrast, the conformation of the N-terminal region, residues 17-20 of A (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) that constitute the binding interface with 17-HSD10, [11] is known to exhibit a random-coil/-helix/-sheet equilibrium that is highly dependent on pH conditions. [61,63,64] At pH 7-8, it has been demonstrated that residues 10-28, containing the putative 17-HSD10 binding interface, are in equilibrium between random coil and -helix conformations.…”

“…Since the discovery that A peptides are found within the mitochondria of AD brains, [11] several attempts have been made to comprehend the mechanisms underpinning A-induced mitochondrial dysfunction, [12][13][14][15][16][17][18][19][20] and to identify receptors which may be involved in this process. [21] Specifically, the observed interaction between mitochondrial proteins with aggregated A peptides has been suggested as a potential pathogenic mechanism contributing to A neurotoxicity in AD.…”

“…[21] Specifically, the observed interaction between mitochondrial proteins with aggregated A peptides has been suggested as a potential pathogenic mechanism contributing to A neurotoxicity in AD. [17][18][19][20][21][22] For instance, the 17-hydroxysteroid dehydrogenase type 10 (17-HSD10) or also commonly known as amyloid-binding alcohol dehydrogenase (ABAD)) [21,[23][24][25][26] constitutes one of such mitochondrial A-interacting proteins. [6,27] 17-HSD10 is a 27 kDa multifunctional enzyme expressed in all cell types and is thought to play a central role in the -oxidation of fatty acids, [24,28] isoleucine degradation, catalysis and oxidation of alcohols and the reduction of aldehydes and ketones.…”

Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales

“…Although the first group to propose mitochondrial functional defects as a mechanism for AD was primarily interested in oxidative stress as a mechanism (Blass and Gibson, 1991), it did not take long for researchers of A␤, by then dominating AD disease pathogenesis, to incorporate the mechanism of mitochondrial dysfunction into their reasoning (Kaneko et al, 1995). This view persists to the present day (Borger et al, 2011) and has remained largely unquestioned despite the implications of the prevalence of TNF in AD brains (section III) and the widely published capacity of this cytokine to induce both A␤PP and A␤ (section IV) and to directly cause mitochondrial dysfunction (see above). Young-Collier et al (2012) found that the reduced expression of mRNA of genes responsible for mitochondrial function in human AD neurons could not be duplicated with 3 days of culture with A␤ 1-42 (instead, expression rose); this might now encourage investigation into other possible mechanisms for the finding.…”