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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, accumulation of the amyloid-β-peptide (Aβ) and synaptic alterations. Treatment with lithium has been shown to provide neuroprotection against several insults, including protection against Aβ neurotoxicity in vitro . Rosiglitazone, a peroxisome proliferator activated receptor-γ agonist, has been shown to attenuate Aβ-peptide neurotoxic effects, including the inflammatory response of microglia and astrocytes. Both types of drugs activate Wnt signaling, a pathway that has been shown to be related to AD. In this study, a double transgenic mouse model, which coexpresses APPswe and the exon 9 deletion of the presenilin 1 (PSEN1) gene, was used to examine, in vivo , the effect of lithium and rosiglitazone on Aβ neurotoxicity. Mice were tested for spatial memory, and their brain samples were used for histochemical and biochemical analysis. In this study, we report that both drugs significantly reduced (1) spatial memory impairment induced by amyloid burden; (2) Aβ aggregates and Aβ oligomers; and (3) astrocytic and microglia activation. They also prevented changes in presynaptic and postsynaptic marker proteins. Finally, both drugs activate Wnt signaling shown by the increase in β-catenin and by the inhibition of the glycogen synthase kinase-3β. We conclude that lithium and rosiglitazone, possibly by the activation of the Wnt signaling pathway, reduce various AD neuropathological markers and may be considered as potential therapeutic agents against the disease.

Current evidence supports the notion that β -amyloid deposits or A β intermediates may be responsible for the pathogenesis in Alzheimer's disease (AD) patients. In the present work, we have assessed the neuroprotective effect of the chronic intraperitoneal administration of a five-amino-acid β -sheet breaker peptide (iA β 5p) on the rat behavioral deficit induced by the intrahippocampal A β -fibrils injection. At 1 month after the injection, animals showed a partial reduction of the amyloid deposits formed and a decreased astrocytic response around the injection site. More importantly, we report that following the iA β 5p treatment, hippocampal-dependent spatial learning paradigms, including the standard Morris water maze and a working memory analysis, showed a significant prevention from impairments induced by A β deposits in the dorsal hippocampus. Thus, it is possible that a noninvasive treatment such as the one presented here with β -sheet breaker peptides may be used as a potential therapy for AD patients.

The major protein constituent of amyloid deposits in Alzheimer's disease (AD) is the amyloid β -peptide (A β ). In the present work, we have determined the effect of hyperforin an acylphloroglucinol compound isolated from Hypericum perforatum (St John's Wort), on A β -induced spatial memory impairments and on A β neurotoxicity. We report here that hyperforin: (1) decreases amyloid deposit formation in rats injected with amyloid fibrils in the hippocampus; (2) decreases the neuropathological changes and behavioral impairments in a rat model of amyloidosis; (3) prevents A β -induced neurotoxicity in hippocampal neurons both from amyloid fibrils and A β oligomers, avoiding the increase in reactive oxidative species associated with amyloid toxicity. Both effects could be explained by the capacity of hyperforin to disaggregate amyloid deposits in a dose and time-dependent manner and to decrease A β aggregation and amyloid formation. Altogether these evidences suggest that hyperforin may be useful to decrease amyloid burden and toxicity in AD patients, and may be a putative therapeutic agent to fight the disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which is probably caused by the cytotoxic effect of the amyloid β -peptide (A β ). We report here molecular changes induced by A β , both in neuronal cells in culture and in rats injected in the dorsal hippocampus with preformed A β fibrils, as an in vivo model of the disease. Results indicate that in both systems, A β neurotoxicity resulted in the destabilization of endogenous levels of β -catenin, a key transducer of the Wnt signaling pathway. Lithium chloride, which mimics Wnt signaling by inhibiting glycogen synthase kinase-3 β promoted the survival of post-mitotic neurons against A β neurotoxicity and recovered cytosolic β -catenin to control levels. Moreover, the neurotoxic effect of A β fibrils was also modulated with protein kinase C agonists/inhibitors and reversed with conditioned medium containing the Wnt-3a ligand. We also examined the spatial memory performance of rats injected with preformed A β fibrils in the Morris water maze paradigm, and found that chronic lithium treatment protected neurodegeneration by rescuing β -catenin levels and improved the deficit in spatial learning induced by A β . Our results are consistent with the idea that A β -dependent neurotoxicity induces a loss of function of Wnt signaling components and indicate that lithium or compounds that mimic this signaling cascade may be putative candidates for therapeutic intervention in Alzheimer's patients.

Heart failure (HF) is a major public health issue affecting more than 26 million people worldwide. HF is the most common cardiovascular disease in elder population; and it is associated with neurocognitive function decline, which represent underlying brain pathology diminishing learning and memory faculties. Both HF and neurocognitive impairment are associated with recurrent hospitalization episodes and increased mortality rate in older people, but particularly when they occur simultaneously. Overall, the published studies seem to confirm that HF patients display functional impairments relating to attention, memory, concentration, learning, and executive functioning compared with age-matched controls. However, little is known about the molecular mechanisms underpinning neurocognitive decline in HF. The present review round step recent evidence related to the possible molecular mechanism involved in the establishment of neurocognitive disorders during HF. We will make a special focus on cerebral ischemia, neuroinflammation and oxidative stress, Wnt signaling, and mitochondrial DNA alterations as possible mechanisms associated with cognitive decline in HF. Also, we provide an integrative mechanism linking pathophysiological hallmarks of altered cardiorespiratory control and the development of cognitive dysfunction in HF patients. Graphical Abstract Main molecular mechanisms involved in the establishment of cognitive impairment during heart failure . Heart failure is characterized by chronic activation of brain areas responsible for increasing cardiac sympathetic load. In addition, HF patients also show neurocognitive impairment, suggesting that the overall mechanisms that underpin cardiac sympathoexcitation may be related to the development of cognitive disorders in HF. In low cardiac output, HF cerebral infarction due to cardiac mural emboli and cerebral ischemia due to chronic or intermittent cerebral hypoperfusion has been described as a major mechanism related to the development of CI. In addition, while acute norepinephrine (NE) release may be relevant to induce neural plasticity in the hippocampus, chronic or tonic release of NE may exert the opposite effects due to desensitization of the adrenergic signaling pathway due to receptor internalization. Enhanced chemoreflex drive is a major source of sympathoexcitation in HF, and this phenomenon elevates brain ROS levels and induces neuroinflammation through breathing instability. Importantly, both oxidative stress and neuroinflammation can induce mitochondrial dysfunction and vice versa. Then, this ROS inflammatory pathway may propagate within the brain and potentially contribute to the development of cognitive impairment in HF through the activation/inhibition of key molecular pathways involved in neurocognitive decline such as the Wnt signaling pathway.

Settlement and recruitment of benthic marine invertebrates are complex processes, determined by the interaction of biotic and abiotic factors which operate at different temporal and spatial scales. This review analyses the settlement process, attempting to integrate aspects related to different levels of organization (i.e. ecological-physiological-molecular). This is important because many factors that act at any of these levels and at different times can explain by themselves the patterns of settlement and/or recruitment of a large number of species. From an ecological perspective, progress has been made in the identification of causal factors of variations in larval availability for settlement. Many physical and ethological factors that act during settlement have, however, not received much attention. Likewise, since the great majority of settlement studies have been carried out at restricted spatial scales, fewer works consider different biological and physical factors acting at different scales simultaneously. Settlement patterns are frequently inferred from recruitment. In this sense, a density-independent action of post-settlement mortality has been considered as prerequisite for this type of inference. This has, however, recently been challenged on the basis that settler-recruit and mortality-settler density relationships change in time. At the physiological-molecular level, different settlement-inducing chemical cues have been identified. Those cues have, however, not yet been characterized to understand better the signal transduction mechanisms involved in larval responses. It is likely that the nervous system is involved. The use of artificial inducers would be useful in studying settlement induction, until more effective natural inducers are isolated and characterized. Although few studies have analysed the acquisition of competence, stages of larval development have been related to changes in protein patterns or enzymatic levels of the nervous system. An inopportune exposure of larvae to inducers may delay settlement and may even have a negative impact on growth and subsequent survival of juveniles.

Human cellular prion protein (PrP C ) is involved in several neurodegenerative disorders; however, its normal function is unknown. We report here that a synthetic peptide corresponding to the four-octarepeat sequence of the PrP C (PrP 59–91 ) protects hippocampal neurons against copper neurotoxic effects in vivo . Using a rat bilateral intrahippocampal injection model, we found that PrP 59–91 protects against copper-induced neurotoxicity, including a recovery in spatial learning performance and a reduced neuronal cell loss and astrogliosis. Previous studies from our laboratory indicated that a tryptophan (Trp) residue plays a key role in the reduction of copper(II) to copper(I); therefore several PrP 59–91 fragments lacking histidine (His) and Trp residues were tested for their capacity to protect from copper toxicity. A PrP 59–91 peptide lacking His residue shows as much neuroprotection as the native peptide; however, PrP 59–91 without Trp residues only partially protected against copper toxicity. The neuroprotective effect not only occurs with PrP 59–91 , in fact a full neuroprotection was also observed using just one octamer of the N-terminal region of prion protein. We conclude that the N-terminal tandem octarepeat of the human PrP C protects neurons against copper toxicity by a differential contribution of the binding (His) and reducing (Trp) copper activities of PrP 59–91 . Our results are consistent with the idea that PrP C function is related to copper homeostasis.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, amyloid-β peptide (Aβ) accumulation and synaptic alterations. Previous studies indicated that hyperforin, a component of the St John's Wort, prevents Aβ neurotoxicity and some behavioral impairments in a rat model of AD. In this study we examined the ability of tetrahydrohyperforin (IDN5607), a stable hyperforin derivative, to prevent the cognitive deficit and synaptic impairment in an in vivo model of AD. In double transgenic APPswe/PSEN1ΔE9 mice, IDN5706 improves memory and prevents the impairment of synaptic plasticity in a dose-dependent manner, inducing a recovery of long-term potentiation. In agreement with these findings, IDN5706 prevented the decrease in synaptic proteins in hippocampus and cortex. In addition, decreased levels of tau hyperphosphorylation, astrogliosis, and total fibrillar and oligomeric forms of Aβ were determined in double transgenic mice treated with IDN5706. In cultured cells, IDN5706 decreased the proteolytic processing of the amyloid precursor protein that leads to Aβ peptide generation. These findings indicate that IDN5706 ameliorates AD neuropathology and could be considered of therapeutic relevance in AD treatment.

Several cellular processes could be targeted if the complex nature of Alzheimers disease (AD) was already understood. Most of AD treatments have been focused on the inhibition of acetylcholinesterase (AChE) in order to raise the levels of its substrate, i.e. the neurotransmitter acetylcholine (ACh), to augment cognitive functions of affected patients. Effectiveness in AChE inhibition and side-effect issues of clinical (tacrine, donepezil, galanthamine and rivastigmine) as well as of novel inhibitors is reviewed here. Novel design methods for the inhibition of AChE include the use of in silico tools to predict the interactions between AChE and the desired compound, both at the active site of the enzyme, responsible of hydrolysing ACh and with the peripheral anionic site (PAS), which has been described as a promoting agent of the amyloid β-peptide (Aβ) aggregation present in the senile plaques of the brain of AD individuals.