BackgroundThe pathogenic road map leading to Alzheimer's disease (AD) is still not completely understood; however, a large body of studies in the last few years supports the idea that beside the classic hallmarks of the disease, namely the accumulation of amyloid-β (Aβ) and neurofibrillary tangles, other factors significantly contribute to the initiation and the progression of the disease. Among them, mitochondria failure, an unbalanced neuronal redox state, and the dyshomeostasis of endogenous metals like copper, iron, and zinc have all been reported to play an important role in exacerbating AD pathology. Given these factors, the endogenous peptide carnosine may be potentially beneficial in the treatment of AD because of its free-radical scavenger and metal chelating properties.MethodologyIn this study, we explored the effect of L-carnosine supplementation in the 3xTg-AD mouse, an animal model of AD that shows both Aβ- and tau-dependent pathology.Principal FindingsWe found that carnosine supplementation in 3xTg-AD mice promotes a strong reduction in the hippocampal intraneuronal accumulation of Aβ and completely rescues AD and aging-related mitochondrial dysfunctions. No effects were found on tau pathology and we only observed a trend toward the amelioration of cognitive deficits.Conclusions and SignificanceOur data indicate that carnosine can be part of a combined therapeutic approach for the treatment of AD.

The overall effect of brain zinc (Zn2+) in the progression and development of Alzheimer's disease (AD) is still not completely understood. Although an excess of Zn2+ can exacerbate the pathological features of AD, a deficit of Zn2+ intake has also been shown to increase the volume of amyloid plaques in AD transgenic mice. In this study, we investigated the effect of dietary Zn2+ supplementation (30 p.p.m.) in a transgenic mouse model of AD, the 3xTg-AD, that expresses both β amyloid (Aβ)- and tau-dependent pathology. We found that Zn2+ supplementation greatly delays hippocampal-dependent memory deficits and strongly reduces both Aβ and tau pathology in the hippocampus. We also evaluated signs of mitochondrial dysfunction and found that Zn2+ supplementation prevents the age-dependent respiratory deficits we observed in untreated 3xTg-AD mice. Finally, we found that Zn2+ supplementation greatly increases the levels of brain-derived neurotrophic factor (BDNF) of treated 3xTg-AD mice. In summary, our data support the idea that controlling the brain Zn2+ homeostasis may be beneficial in the treatment of AD.

Qu et al. present the first evidence that mDia1-mediated stabilization of dynamic microtubules (MTs) and induction of tubulin posttranslational modifications drive tau hyperphosphorylation and synaptotoxicity, providing a novel target for therapy and the first mechanistic explanation as to why a dynamic MT cytoskeleton must be maintained to prevent neurodegenerative disease.

Summary Prior studies suggest that the transcription factor ATF4 negatively regulates synaptic plastic and memory. By contrast, we provide evidence from direct in vitro and in vivo knockdown of ATF4 in rodent hippocampal neurons and from ATF4 null mice that implicate ATF4 as essential for normal synaptic plasticity and memory. In particular, hippocampal ATF4 down-regulation produces deficits in long-term spatial memory and behavioral flexibility without affecting associative memory or anxiety-like behavior. ATF4 knockdown or loss also causes profound impairment of both long-term potentiation (LTP) and long-term depression (LTD) as well as decreased glutamatergic function. We conclude that ATF4 is a key regulator of the physiological state necessary for neuronal plasticity and memory.

No abstract