Valerio Frazzini

Effects of dietary supplementation of carnosine on mitochondrial dysfunction, amyloid pathology, and cognitive deficits in 3xTg-AD mice.

Background The pathogenic road map leading to Alzheimers 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. Methodology In 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 Findings We 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 Significance Our data indicate that carnosine can be part of a combined therapeutic approach for the treatment of AD.

New therapeutic targets in Alzheimer's disease: brain deregulation of calcium and zinc

The molecular determinants of Alzheimers (AD) disease are still not completely known; however, in the past two decades, a large body of evidence has indicated that an important contributing factor for the disease is the development of an unbalanced homeostasis of two signaling cations: calcium (Ca2+) and zinc (Zn2+). Both ions serve a critical role in the physiological functioning of the central nervous system, but their brain deregulation promotes amyloid-β dysmetabolism as well as tau phosphorylation. AD is also characterized by an altered glutamatergic activation, and glutamate can promote both Ca2+ and Zn2+ dyshomeostasis. The two cations can operate synergistically to promote the generation of free radicals that further intracellular Ca2+ and Zn2+ rises and set the stage for a self-perpetuating harmful loop. These phenomena can be the initial steps in the pathogenic cascade leading to AD, therefore, therapeutic interventions aiming at preventing Ca2+ and Zn2+ dyshomeostasis may offer a great opportunity for disease-modifying strategies.

Combination Training in Aging Individuals Modifies Functional Connectivity and Cognition, and Is Potentially Affected by Dopamine-Related Genes

Background Aging is a major co-risk factor in many neurodegenerative diseases. Cognitive enrichment positively affects the structural plasticity of the aging brain. In this study, we evaluated effects of a set of structured multimodal activities (Combination Training; CT) on cognitive performances, functional connectivity, and cortical thickness of a group of healthy elderly individuals. CT lasted six months. Methodology Neuropsychological and occupational performances were evaluated before and at the end of the training period. fMRI was used to assess effects of training on resting state network (RSN) functional connectivity using Independent Component Analysis (ICA). Effects on cortical thickness were also studied. Finally, we evaluated whether specific dopamine-related genes can affect the response to training. Principal Findings Results of the study indicate that CT improves cognitive/occupational performances and reorganizes functional connectivity. Intriguingly, individuals responding to CT showed specific dopamine-related genotypes. Indeed, analysis of dopamine-related genes revealed that carriers of DRD3 ser9gly and COMT Val158Met polymorphisms had the greatest benefits from exposure to CT. Conclusions and Significance Overall, our findings support the idea that exposure to a set of structured multimodal activities can be an effective strategy to counteract aging-related cognitive decline and also indicate that significant capability of functional and structural changes are maintained in the elderly.

Effects of non-pharmacological or pharmacological interventions on cognition and brain plasticity of aging individuals.

Brain aging and aging-related neurodegenerative disorders are major health challenges faced by modern societies. Brain aging is associated with cognitive and functional decline and represents the favourable background for the onset and development of dementia. Brain aging is associated with early and subtle anatomo-functional physiological changes that often precede the appearance of clinical signs of cognitive decline. Neuroimaging approaches unveiled the functional correlates of these alterations and helped in the identification of therapeutic targets that can be potentially useful in counteracting age-dependent cognitive decline. A growing body of evidence supports the notion that cognitive stimulation and aerobic training can preserve and enhance operational skills in elderly individuals as well as reduce the incidence of dementia. This review aims at providing an extensive and critical overview of the most recent data that support the efficacy of non-pharmacological and pharmacological interventions aimed at enhancing cognition and brain plasticity in healthy elderly individuals as well as delaying the cognitive decline associated with dementia.

Altered Kv2.1 functioning promotes increased excitability in hippocampal neurons of an Alzheimer’s disease mouse model

Altered neuronal excitability is emerging as an important feature in Alzheimer’s disease (AD). Kv2.1 potassium channels are important modulators of neuronal excitability and synaptic activity. We investigated Kv2.1 currents and its relation to the intrinsic synaptic activity of hippocampal neurons from 3xTg-AD (triple transgenic mouse model of Alzheimers disease) mice, a widely employed preclinical AD model. Synaptic activity was also investigated by analyzing spontaneous [Ca2+]i spikes. Compared with wild-type (Non-Tg (non-transgenic mouse model)) cultures, 3xTg-AD neurons showed enhanced spike frequency and decreased intensity. Compared with Non-Tg cultures, 3xTg-AD hippocampal neurons revealed reduced Kv2.1-dependent Ik current densities as well as normalized conductances. 3xTg-AD cultures also exhibited an overall decrease in the number of functional Kv2.1 channels. Immunofluorescence assay revealed an increase in Kv2.1 channel oligomerization, a condition associated with blockade of channel function. In Non-Tg neurons, pharmacological blockade of Kv2.1 channels reproduced the altered pattern found in the 3xTg-AD cultures. Moreover, compared with untreated sister cultures, pharmacological inhibition of Kv2.1 in 3xTg-AD neurons did not produce any significant modification in Ik current densities. Reactive oxygen species (ROS) promote Kv2.1 oligomerization, thereby acting as negative modulator of the channel activity. Glutamate receptor activation produced higher ROS levels in hippocampal 3xTg-AD cultures compared with Non-Tg neurons. Antioxidant treatment with N-Acetyl-Cysteine was found to rescue Kv2.1-dependent currents and decreased spontaneous hyperexcitability in 3xTg-AD neurons. Analogous results regarding spontaneous synaptic activity were observed in neuronal cultures treated with the antioxidant 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox). Our study indicates that AD-related mutations may promote enhanced ROS generation, oxidative-dependent oligomerization, and loss of function of Kv2.1 channels. These processes can be part on the increased neuronal excitability of these neurons. These steps may set a deleterious vicious circle that eventually helps to promote excitotoxic damage found in the AD brain.

Medium-chain plasma acylcarnitines, ketone levels, cognition, and gray matter volumes in healthy elderly, mildly cognitively impaired, or Alzheimer's disease subjects

Aging, amyloid deposition, and tau-related pathology are key contributors to the onset and progression of Alzheimers disease (AD). However, AD is also associated with brain hypometabolism and deficits of mitochondrial bioenergetics. Plasma acylcarnitines (ACCs) are indirect indices of altered fatty acid beta-oxidation, and ketogenesis has been found to be decreased on aging. Furthermore, in elderly subjects, alterations in plasma levels of specific ACCs have been suggested to predict conversion to mild cognitive impairment (MCI) or AD. In this study, we assayed plasma profiles of ACCs in a cohort of healthy elderly control, MCI subjects, and AD patients. Compared with healthy controls or MCI subjects, AD patients showed significant lower plasma levels of several medium-chain ACCs. Furthermore, in AD patients, these lower concentrations were associated with lower prefrontal gray matter volumes and the presence of cognitive impairment. Interestingly, lower levels of medium-chain ACCs were also found to be associated with lower plasma levels of 2-hydroxybutyric acid. Overall, these findings suggest that altered metabolism of medium-chain ACCs and impaired ketogenesis can be metabolic features of AD.

Characterisation of element profile changes induced by long-term dietary supplementation of zinc in the brain and cerebellum of 3xTg-AD mice by alternated cool and normal plasma ICP-MS

Metal dyshomeostasis plays a crucial role in promoting several neurodegenerative diseases including Alzheimers disease (AD), a condition that has been linked to deregulation of brain levels of Al, Fe, Mn, Cu, and Zn. Thus, quantitative multi-element profiling of brain tissues from AD models can be of great value in assessing the pathogenic role of metals as well as the value of therapeutic interventions aimed at restoring metal homeostasis in the brain. In this study, we employed low resolution inductively coupled plasma mass spectrometry (ICP-MS) to evaluate levels of ultra-trace, trace, and major elements in brains and cerebella of 3xTg-AD mice, a well characterized transgenic (Tg) AD model. This method is based on alternated cool and hot plasma ICP-MS. The essay fulfilled analytical requirements for the quantification of 14 elements in the Central Nervous System (CNS) of our Tg model. Quantification of Li, Al, Cr, and Co, a procedure that requires a pre-concentration step, was validated by high resolution ICP-MS. Changes in element profiles occurring in 3xTg-AD mice were compared to the ones observed in wild type (WT) mice. We also investigated variations in element profiles in 3xTg-AD mice receiving a long-term (17 months) dietary supplementation of Zn. Our data indicate that, compared to WT animals, 3xTg-AD mice displayed signs of altered brain metal homeostasis. We also found that long-term Zn administration promoted decreased brain levels of some metals (K, Ca, and Fe) and restored levels of Al, Cr, and Co to values found in WT mice.