The consequences of mitochondrial amyloid β-peptide in Alzheimer's disease

Abstract

The Abeta (amyloid-beta peptide) has long been associated with Alzheimer's disease, originally in the form of extracellular plaques. However, in the present paper we review the growing evidence for the role of soluble intracellular Abeta in the disease progression, with particular reference to Abeta found within the mitochondria. Once inside the cell, Abeta is able to interact with a number of targets, including the mitochondrial proteins ABAD (amyloid-binding alcohol dehydrogenase) and CypD (cyclophilin D), which is a component of the mitochondrial permeability transition pore. Interference with the normal functions of these proteins results in disruption of cell homoeostasis and ultimately cell death. The present review explores the possible mechanisms by which cell death occurs, considering the evidence presented on a molecular, cellular and in vivo level.

Hopeahainol A attenuates memory deficits by targeting β‐amyloid in APP/PS1 transgenic mice

“…Ab aggregation is neurotoxic and may be the primary toxic species in AD (Muirhead et al, 2010). Therefore, prevention of Ab aggregation and attenuation of its neurotoxicity have been the focus of AD therapies.…”

“…Neurotoxicity resulting from increased levels of intracellular amyloid beta (Ab), predominantly Ab 1-42 and its aggregates, plays an important role in cognitive impairment in Alzheimer's disease (AD; Cleary et al, 2005;Muirhead et al, 2010). Recent evidence indicates that mitochondrial dysfunction is a critical feature of Ab-induced neurotoxicity, that is, reduced brain metabolism, oxidative stress and calcium dysregulation, collaborate with each other to form a deadly mitochondrial spiral (Mutisya et al, 1994;Smith et al, 2000).…”

A Direct Interaction Between Mitochondrial Proteins and Amyloid-β Peptide and its Significance for the Progression and Treatment of Alzheimer’s Disease

“…This discrepancy can be explained by the rapid Aβ degradation occurring in the matrix by mitochondrial proteases (e.g. PreP or IDE) [13][14][15]. Also the origin of mitochondrial Aβ is still a matter of debate.…”

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

“…[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. [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.…”

“…[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.…”