A humanin derivative, S14G‐HN, prevents amyloid‐β‐induced memory impairment in mice

Abstract

Humanin (HN) is a 24-amino acid peptide that protects neuronal cells from death caused by Alzheimer's disease (AD)-related genes and amyloid-beta (Abeta). Multiple studies have revealed its biochemical and neuroprotective characteristics in vitro; however, little has been known regarding whether HN is effective in vivo in AD model systems. We examined the effect of S14G-HN, a 1,000-fold more potent derivative of HN in vitro, on amnesia induced by Abeta25-35 in mice. The Y-maze test revealed that at least 50 pmol of S14G-HN by intracerebroventricular injection prevented Abeta-induced impairment of short-term/spatial working memory; however, 5 nmol of S14A-HN, a neuroprotection-defective mutant in vitro, did not prevent Abeta-induced amnesia. These results are in agreement with the structure-function correlation shown previously in vitro. In the water-finding task, S14G-HN prevented prolongation of finding latency (the time to find water) observed in Abeta-amnesic mice, indicating that S14G-HN also blocked Abeta-induced impairment of latent learning. In accordance with these observations, immunohistochemical analysis showed that S14G-HN sustained the number of cholinergic neurons in the basal forebrain and the striata nearly to the normal level. Furthermore, genistein, a specific inhibitor of tyrosine kinases, blocked recovery from scopolamine-induced amnesia by S14G-HN, suggesting that certain tyrosine kinase(s) are involved in the inhibitory function of S14G-HN in vivo. Taking these findings together, we conclude that S14G-HN has rescue activity against memory impairment caused by AD-related insults in vivo by activating the same intracellular neuroprotective machinery as elucidated previously in vitro.

Alleviation of Aβ-induced cognitive impairment by ultrasound-mediated gene transfer of HGF in a mouse model

“…In this model, loss of cholinergic neurons was induced by Ab injection. 18 Indeed, we confirmed that injection of Ab(1-40) significantly induced loss of cholinergic neurons in the basal forebrain. However, there was no significant increase in the number of cholinergic neurons in mice transfected with the HGF gene as compared with mice transfected with control vector (data not shown).…”

“…Intracerebroventricular administration was carried out in accordance with the procedure previously described. 18 Briefly, mice were anesthetized with isoflurane gas and xylazine and ketamine, and Ab(1-40) (200 pmol per 5 ml) was injected intracerebroventricularlly into mice, aimed at 1-1.5 mm lateral to the left of the midline, 0.5 mm posterior to the bregma and 3 mm depth using a 100-ml Hamilton syringe with a 27-gauge needle.…”

Mesenchymal stem cells enhance autophagy and increase β-amyloid clearance in Alzheimer disease models

“…Animals were acclimated to a climate-controlled room with a constant 12 h light/dark cycle (12 h on, 12 h off) for a week prior to the initiation of drug administration. At 6 weeks of age, the ICR mice received an intracerebroventricular injection of Aβ (400 ρmol/mouse) or control solution (PBS) as described previously, 55,56 with minor modifications. Briefly, mice were anesthetized with isoflurane gas, and Aβ (400 ρmol/2 uL) or control solution (PBS) was slowly injected (0.2 uL/min) bilaterally into the lateral ventricles (0.2 mm posterior to bregma, 1.0 mm lateral to midline, and 3.1 mm ventral to the brain surface) using a stainless-steel injection needle (26 gauge) connected to a 10 μL Hamilton micro-syringe (Hamilton).…”

Cognitive Deficit in Amyloid-β–Injected Mice Was Improved by Pretreatment With a Low Dose of Telmisartan Partly Because of Peroxisome Proliferator-Activated Receptor-γ Activation

“…19 Swimming was video tracked, and latency, path length, swim speed, and cumulative distance from the platform were analyzed by AnyMaze (Stoelting Co).…”