Humanin attenuates Alzheimer-like cognitive deficits and pathological changes induced by amyloid β-peptide in rats

Abstract

Amyloid β-peptide (Aβ) has been implicated as a key molecule in the neurodegenerative cascades of Alzheimer's disease (AD). Humanin (HN) is a secretory peptide that inhibits the neurotoxicity of Aβ. However, the mechanism(s) by which HN exerts its neuroprotection against Aβ-induced ADlike pathological changes and memory deficits are yet to be completely defined. In the present study, we provided evidence that treatment of rats with HN increases the number of dendritic branches and the density of dendritic spines, and upregulates pre-and post-synaptic protein levels; these effects lead to enhanced long-term potentiation and amelioration of the memory deficits induced by Aβ 1-42 . HN also attenuated Aβ 1-42 -induced tau hyperphosphorylation, apparently by inhibiting the phosphorylation of Tyr307 on the inhibitory protein phosphatase-2A (PP2A) catalytic subunit and thereby activating PP2A. HN also inhibited apoptosis and reduced the oxidative stress induced by Aβ 1-42 . These fi ndings provide novel mechanisms of action for the ability of HN to protect against Aβ 1-42 -induced AD-like pathological changes and memory defi cits.

[Gly14]-Humanin Protects Against Amyloid β Peptide-Induced Impairment of Spatial Learning and Memory in Rats

“…It has been reported that HN increases the ATP levels in serum-deprived human lymphocytes, TE671 muscle cells, and SKN-MC neural cells [21]. It also inhibits apoptosis and reduces the oxidative stress induced by Ab 1-42 [22]. The highly selective effect of HN on cell death associated with AD indicates that it could be promising for AD therapy [23,24].…”

Murine maternal dietary restriction affects neural Humanin expression and cellular profile

“…HN has been shown to be neuroprotective in several models of adult neurologic disease. It is most extensively studied in murine models of Alzheimer's disease, where exogenous administration has been shown to inhibit Aβ neurotoxicity and improve functional outcomes (Chai et al, ). Similar findings have been seen with adult models of stroke and amyotrophic lateral sclerosis (Matsuoka, Hashimoto, Aiso, & Nishimoto, ; Xu, Chua, Gao, Hamdy, & Chua, ).…”

Regulation of Antioxidant Defenses, DNA Damage Repair, the Immune Response, and Neuroprotection During Hibernation in the Thirteen-Lined Ground Squirrel

“…This is validated by the precipitous drop in the levels of plasma ascorbate (a powerful antioxidant) over the same timeframe [206]. Humanin has been shown to be a key modulator of oxidative stress via the induction of antioxidant enzymes such as SOD [227,231,254] and glutathione peroxidase [226] as well as mediating chaperone-mediated autophagy [230], suggesting a comparable action for s-humanin. Additionally, studies have shown that oxidative stress is widely involved in the development of various neuropathologies that can be counteracted by the effects of humanin.…”

“…Additionally, it has been shown that hibernating ground squirrels do not appear to show any significant neurodegeneration upon exiting from a torpor bout, making the squirrel an excellent model to contribute to the study of neurological disorders such as Alzheimer's [15]. As previously mentioned, the neurons in squirrel brain retract and reduce in size and thereby causing its activation [226]. Therefore, increases in both s-humanin transcript and protein levels in the cortex are highly indicative of its protective function for areas of highlevel cognition and survival.…”

“…It has been proposed that humanin can suppress AD by reducing neuronal cell death caused by Aβ accumulation [226] and oxidative damage [227][228][229][230]. Humanin exerts this effect by mediating the remodeling of dendritic structural complexities and by preventing mitochondrial dysfunctions.…”