SS31, a Small Molecule Antioxidant Peptide, Attenuates β-Amyloid Elevation, Mitochondrial/Synaptic Deterioration and Cognitive Deficit in SAMP8 Mice

Abstract

Mitochondrial dysfunction, oxidative stress and β -amyloid (Aβ) formation are thought to cause neuronal and synaptic degeneration underlying cognitive decline in Alzheimer's disease (AD). The senescence-accelerated mouse-prone 8 (SAMP8) mice have been used as an animal model for mechanistic and translational research for AD. In the present study we characterized mitochondrial and synaptic alterations in SAMP8 mice relative to SAMR1control mice and explored a protective effect of the small molecule peptide SS31, a cell membrane penetrant antioxidant, on mitochondrial and synaptic protein integrity as well as cognitive performance. Electron microscopic analysis revealed mitochondrial/synaptic deterioration in 10 months-old SAMP8 relative to SAMR1 mice, with the changes in the former rescued following 8 weeks treatment with SS31 (5 mg/kg/day, i.p.). Elevation of Aβ42, mitochondrial fission protein (DLP1, Fis1) and matrix protein cyclophilin D (CypD), and reductions of mitochondrial fusion protein (Mfn2) and synaptic (i.e., synaptophysin, postsynaptic density protein 95 and growth associated protein 43) proteins, were detected in hippocampal lysates in SAMP8 mice relative to SAMR1. The above altered protein expressions in the SAMP8 mouse brain were restored with the SS31 treatment. Moreover, the SS31 treatment rescued learning and memory deficits detected in 10 month-old SAMP8 mice. Together, the findings suggest that this mitochondria-targeting antioxidant peptide may be of potential utility for AD therapy, with its pharmacological efficacy involves lowering of central Aβ levels and protection of mitochondrial homeostasis and synaptic integrity, which may help slow down cognitive decline.

SS31 Ameliorates age-related activation of NF-κB signaling in senile mice model, SAMP8

“…Accelerated aging elicits cytoprotective and antioxidant response in hippocampus by activating Nrf2/ARE pathway gradually. Nrf2 is a principal mediator for primary cellular defense against cytotoxic effects for the central nervous system (CNS), including pathways for DNA repair, molecular chaperones, antioxidants, anti-inflammatory response, and proteasome systems [22]. The Nrf2 dependent self-protective antioxidant response is a complex and highly orchestrated pathophysiological process.…”

“…In our recent study, the SAMP8 mice showed cognitive decline and abnormal mitochondrial fission/fusion proteins compared to SAMR1 at 10-month-old. After the treatment of SS31 for 8 weeks, the spatial learning and memory skills were improved and the mitochondrial homeostasis was maintained [22]. However, it is unknown whether application of this compound exerted protective effects through NF-κB signaling and Nrf2/ARE pathway.…”

Synaptic Pruning in Alzheimer’s Disease: Role of the Complement System

“…Elippocampal lysates in SAMP8 mice relative to SAMR1 revealed elevation of beta amyloid 42, mitochondrial fission protein (DLP1, Fis1) and matrix protein cyclophilin D (CypD). In addition, lysates showed reductions of mitochondrial fusion protein (Mfn2) and synaptic (i.e., synaptophysin, postsynaptic density protein 95 and growth associated protein 43) proteins [ 78 ]. These altered protein expressions in the SAMP8 mouse brain were restored with the SS31 treatment.…”

“…Moreover, the SS31 treatment rescued learning and memory deficits detected in10 month-old SAMP8 mice. Study authors conclude these findings suggest that this mitochondria-targeting antioxidant peptide may be of potential utility for AD therapy, including a possible lowering of central Aβ levels and protection of mitochondrial homeostasis and synaptic integrity, which may help slow down cognitive decline [ 78 ]. Neurexinl (Nrxnl) and Neuroligin3 (Nlgn3) are cell adhesion proteins, which are important to age-related synaptic plasticity decline.…”

Linking mitochondrial dysfunction, metabolic syndrome and stress signaling in Neurodegeneration

“…A small molecule antioxidant peptide attenuates Aβ elevation, mitochondrial/synaptic deterioration and cognitive deficit in SAMP8 mice AD [138] STX A novel membrane estrogen receptor ligand, attenuates mitochondrial dysfunction, cell death, dendritic simplification and synaptic loss induced by Aβ AD [139] MitoQ Reduces oxidative stress, free radicals and Ca (2+)-burden in mitochondria that causes decreased ATP production. Further, altered Mitochondrial dynamic and trafficking are also targeted by MitoQ AD and MetS [140,141] Oryzanols, Tocopherols and Tocotrienols…”