Abnormal mitochondrial dynamics and synaptic degeneration as early events in Alzheimer's disease: Implications to mitochondria-targeted antioxidant therapeutics

Abstract

Synaptic pathology and mitochondrial oxidative damage are early events in Alzheimer’s disease (AD) progression. Loss of synapses and synaptic damage are the best correlate of cognitive deficits found in AD patients. Recent research on amyloid bet (Aβ) and mitochondria in AD revealed that Aβ accumulates in synapses and synaptic mitochondria, leading to abnormal mitochondrial dynamics and synaptic degeneration in AD neurons. Further, recent studies using live-cell imaging and primary neurons from amyloid beta precursor protein (AβPP) transgenic mice revealed that reduced mitochondrial mass, defective axonal transport of mitochondria and synaptic degeneration, indicating that Aβ is responsible for mitochondrial and synaptic deficiencies. Tremendous progress has been made in studying antioxidant approaches in mouse models of AD and clinical trials of AD patients. This article highlights the recent developments made in Aβ-induced abnormal mitochondrial dynamics, defective mitochondrial biogenesis, impaired axonal transport and synaptic deficiencies in AD. This article also focuses on mitochondrial approaches in treating AD, and also discusses latest research on mitochondria-targeted antioxidants in AD.

Alzheimer’s Disease: Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines

“…The treatment of rodent hippocampal neurons with Aβ or the presence of a PS1 or AβPP mutation resulted in the significant reduction of anterograde mitochondrial transport, thereby considerably accompanying to synaptic dysfunction characteristic of AD, which findings were confirmed in mouse model of AD and by the post mortem analysis of brains from AD patients [15, [79][80][81][82][83][84][85][86]. It was hypothesized that alterations in synaptic mitochondria develops earlier than in non-synaptic mitochondria [87]. It seems that tau is required for Aβ-induced impairment of axonal transport, which process is presumably initiated via the activation of NMDARs, glycogen synthase kinase 3β (GSK3β), and casein kinase 2 (CK2) [84,88,89].…”

Molecular Strategies for Targeting Antioxidants to Mitochondria: Therapeutic Implications

“…This moiety is believed to scavenge OH and ONOO -, and possibly HOCl and peroxyl radicals, but a direct reaction with O 2 -or H 2 O 2 seems unlikely. The specific location of these residues does not appear to be significant, as SS-31 is as effective as SS-02 in scavenging H 2 O 2 and inhibiting LDL oxidation (261). SS-peptides have been reported to be beneficial against the conditions of oxidative stress both in cellular models of disease and in isolated mitochondria, with SS-31 proving to be the most efficient (187,352,378).…”

“…Importantly, SS-31 administration largely prevented mitochondrial oxidative damage and the process of autophagy in the heart induced by chronic pressure overload. Several studies using neurons treated with Ab25-35 peptide and primary neurons from Tg2576 mice (AbPP transgenic) have highlighted the potential of SS-31 for treatment of AD (261). Primary neurons from AbPP mice present decreased anterograde mitochondrial movement, increased mitochondrial fission and decreased fusion, abnormal mitochondrial and synaptic proteins, and defective mitochondrial function when compared with wild-type neurons.…”

Senescence-accelerated OXYS rats: A model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease

“…Several factors, including lifestyle, diet, environmental exposure, apolipoprotein allele E4 (ApoE), and several other genetic variants have been reported to be involved in late-onset AD. 14 It is noteworthy that AD frequently develops against a background of complex manifestations of aging and along with other age-related diseases, including agerelated macular degeneration (AMD). AMD is a progressive, complex disease and is the most common cause of blindness in the aging population.…”