Inhibition of Amyloid-β (Aβ) Peptide-Binding Alcohol Dehydrogenase-Aβ Interaction Reduces Aβ Accumulation and Improves Mitochondrial Function in a Mouse Model of Alzheimer's Disease

Abstract

Amyloid-β (Aβ) peptide-binding alcohol dehydrogenase (ABAD), an enzyme present in neuronal mitochondria, exacerbates Aβ-induced cell stress. The interaction of ABAD with Aβ exacerbates Aβ-induced mitochondrial and neuronal dysfunction. Here, we show that inhibition of the ABAD-Aβ interaction, using a decoy peptide (DP) in vitro and in vivo, protects against aberrant mitochondrial and neuronal function and improves spatial learning/memory. Intraperitoneal administration of ABAD-DP [fused to the transduction of human immunodeficiency virus 1-transactivator (Tat) protein and linked to the mitochondrial targeting sequence (Mito) (TAT-mito-DP) to transgenic APP mice (Tg mAPP)] blocked formation of ABAD-Aβ complex in mitochondria, increased oxygen consumption and enzyme activity associated with the mitochondrial respiratory chain, attenuated mitochondrial oxidative stress, and improved spatial memory. Similar protective effects were observed in Tg mAPP mice overexpressing neuronal ABAD decoy peptide (Tg mAPP/mito-ABAD). Notably, inhibition of the ABAD-Aβ interaction significantly reduced mitochondrial Aβ accumulation. In parallel, the activity of mitochondrial Aβ-degrading enzyme PreP (presequence peptidase) was enhanced in Tg mAPP mitochondria expressing the ABAD decoy peptide. These data indicate that segregating ABAD from Aβ protects mitochondria/neurons from Aβ toxicity; thus, ABAD-Aβ interaction is an important mechanism underlying Aβ-mediated mitochondrial and neuronal perturbation. Inhibitors of ABAD-Aβ interaction may hold promise as targets for the prevention and treatment of Alzheimer’s disease.

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

“…In fact, the inhibition of the Aβ-ABAD interaction has been shown to reduce Aβ accumulation and to improve mitochondrial function in transgenic mice and neuroblastoma cells (Lim et al, 2011;Yao et al, 2011). ABAD converts estrone to estradiol, a key antioxidant compound for neurone survival whose intracellular levels are decreased due to the interaction between Aβ and ABAD, a phenomenon that may contribute to Aβ-induced toxicity (Yang et al 2007;Lim et al, 2011).…”

Towards Alzheimer's root cause: ECSIT as an integrating hub between oxidative stress, inflammation and mitochondrial dysfunction

“…Ab can directly affect respiration, with a consequent increase in ROS production. Interactions of Ab with mitochondrial proteins such as amyloid binding alcohol dehydrogenase (ABAD) exacerbate the toxic effects on mitochondrial and neuronal functioning [31] (Fig. 2).…”

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

“…In addition, our study also demonstrated that HopA could not only bind to the C-terminal of Ab 1-42 directly and decrease the ABAD-Ab 1-42 interaction, but also restored ABAD activity without changing its expression. Interestingly, an ABAD decoy peptide (ABAD-DP) alleviates cognitive dysfunction in Tg mAPP/ABAD mice by restraining the ABADAb interaction (Yao et al, 2011), which indicates that ABAD-Ab interaction might be an effective target for the treatment of AD. Furthermore, HopA protected the synaptic function and LTP induction in APP/PS1 mice, which was accompanied by the improvement of spatial memory performance.…”

“…Specifically, the interaction between Ab and ABAD decreases the activity of ABAD and causes mitochondrial dysfunction in patients with AD and transgenic mouse models of AD (Takuma et al, 2005). An ABAD decoy peptide with the capability of specifically disrupting ABAD-Ab interaction suppresses Ab-mediated mitochondrial toxicity (Yao et al, 2011), suggesting that this interaction may be a promising target for therapeutic intervention in AD.…”