Cyclophilin D deficiency improves mitochondrial function and learning/memory in aging Alzheimer disease mouse model

Abstract

Mitochondrial stress is one of the early features of Alzheimer disease (AD). Mitochondrial Aβ has been linked to mitochondrial toxicity. Our recent study demonstrated that cyclophilin D (CypD) mediated mitochondrial permeability transition pore (mPTP) is an important mechanism for neuronal and synaptic stress induced by both Aβ and oxidative stress. In transgenic AD-type mice overexpressing mutant amyloid precursor protein (APP) and Aβ (mAPP), CypD deficiency improves mitochondrial and synaptic function and learning/memory up to 12 months old. Here we provide evidence of the protective effects of CypD deficiency in aged AD mice (22–24 months). CypD deficient mAPP mice demonstrate less calcium-induced mitochondrial swelling, increased mitochondrial calcium uptake capacity, preserved mitochondrial respiratory function and improved spatial learning/memory even in old age (known to be the age for late stage AD pathology and synaptic dysfunction). These data demonstrate that abrogation of CypD results in persistent life-long protection against Aβ toxicity in an Alzheimer’s disease mouse model, thereby suggesting that blockade of CypD may be of benefit for Alzheimer disease treatment.

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.…”

Mitochondria and aging: A role for the mitochondrial transition pore?

“…CypD binds to the Aβ peptide, and Aβ peptide–CypD complexes were isolated from patients with Alzheimer's disease and transgenic mice (Du, Guo, Zhang, Rydzewska, & Yan, 2011; Du et al., 2008). These complexes potentiate mitochondrial, neuronal, and synaptic stress, and genetic deletion of CypD protects the brain from Aβ‐induced neuronal degeneration (Du et al., 2008, 2014; Guo et al., 2013).…”

Role of Mitochondrial Amyloid-β in Alzheimer's Disease

“…These observations led us to consider a role of intracellular Aβ. Notably, recent studies have highlighted the role of mitochondrial Aβ in AD pathogenesis [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28].…”