Sildenafil restores cognitive function without affecting β-amyloid burden in a mouse model of Alzheimer's disease

Abstract BACKGROUND AND PURPOSE: Inhibitors of phosphodiesterase 5 (PDE5) affect signalling pathways by elevating cGMP, which is a second messenger involved in processes of neuroplasticity. In the present study, the effects of the PDE5 inhibitor, sildenafil, on the pathological features of Alzheimer's disease and on memory-related behaviour were investigated. EXPERIMENTAL APPROACH: Sildenafil was administered to the Tg2576 transgenic mouse model of Alzheimer's disease and to age-matched negative littermates (controls). Memory function was analysed using the Morris water maze test and fear conditioning tasks. Biochemical analyses were performed in brain lysates from animals treated with saline or with sildenafil. KEY RESULTS: Treatment of aged Tg2576 animals with sildenafil completely reversed their cognitive impairment. Such changes were accompanied in the hippocampus by a reduction of tau hyperphosphorylation and a decrease in the activity of glycogen synthase kinase 3β (GSK3β) and of cyclin-dependent kinase 5 (CDK5) (p25/p35 ratio). Moreover, sildenafil also increased levels of brain-derived neurotrophic factor (BDNF) and the activity-regulated cytoskeletal-associated protein (Arc) in the hippocampus without any detectable modification of brain amyloid burden. CONCLUSIONS AND IMPLICATIONS: Sildenafil improved cognitive functions in Tg2576 mice and the effect was not related to changes in the amyloid burden. These data further strengthen the potential of sildenafil as a therapeutic agent for Alzheimer's disease

Neuroprotective effect of non-viral gene therapy treatment based on tetanus toxin C-fragment in a severe mouse model of spinal muscular atrophy

Spinal muscular atrophy (SMA) is a hereditary childhood disease that causes paralysis and progressive degeneration of skeletal muscles and spinal motor neurons. SMA is associated with reduced levels of full-length Survival of Motor Neuron (SMN) protein, due to mutations in the Survival of Motor Neuron 1 gene. Nowadays there are no effective therapies available to treat patients with SMA, so our aim was to test whether the non-toxic carboxy-terminal fragment of tetanus toxin heavy chain (TTC), which exhibits neurotrophic properties, might have a therapeutic role or benefit in SMA. In this manuscript, we have demonstrated that TTC enhance the SMN expression in motor neurons "in vitro" and evaluated the effect of intramuscular injection of TTCencoding plasmid in the spinal cord and the skeletal muscle of SMNdelta7 mice. For this purpose, we studied the weight and the survival time, as well as, the survival and cell death pathways and muscular atrophy. Our results showed that TTC treatment reduced the expression of autophagy markers (Becn1, Atg5, Lc3, and p62) and proapoptotic genes such as Bax and Casp3 in spinal cord. In skeletal muscle, TTC was able to downregulate the expression of the main marker of autophagy, Lc3, to wild-type levels and the expression of the apoptosis effector protein, Casp3. Regarding the genes related to muscular atrophy (Ankrd1, Calm1, Col19a1, Fbox32, Mt2, Myod1, NogoA, Pax7, Rrad, and Sln), TTC suggest a compensatory effect for muscle damage response, diminished oxidative stress and modulated calcium homeostasis. These preliminary findings suggest the need for further experiments to depth study the effect of TTC in SMA disease

Rosiglitazone Rescues Memory Impairment in Alzheimer's Transgenic Mice: Mechanisms Involving a Reduced Amyloid and Tau Pathology

Clinical studies suggest that agonists at peroxisome proliferator-activated receptor gamma (PPARγ) may exert beneficial effects in patients with mild-to-moderate Alzheimer's disease (AD), but the mechanism for the potential therapeutic interest of this class of drugs has not yet been elucidated. Here, in mice overexpressing mutant human amyloid precursor protein, we found that chronic treatment with rosiglitazone, a high-affinity agonist at PPARγ, facilitated β-amyloid peptide (Aβ) clearance. Rosiglitazone not only reduced Aβ burden in the brain but, importantly, almost completely removed the abundant amyloid plaques observed in the hippocampus and entorhinal cortex of 13-month-old transgenic mice. In the hippocampus, neuropil threads containing phosphorylated tau, probably corresponding to dystrophic neurites, were also decreased by the drug. Rosiglitazone switched on the activated microglial phenotype, promoting its phagocytic ability, reducing the expression of proinflammatory markers and inducing factors for alternative differentiation. The decreased amyloid pathology may account for the reduction of p-tau-containing neuropil threads and for the rescue of impaired recognition and spatial memory in the transgenic mice. This study provides further insights into the mechanisms for the beneficial effect of rosiglitazone in AD patients

Immunomodulatory properties of carvone inhalation and Its effects on contextual fear memory in mice

A complex network of interactions exists between the immune, the olfactory, and the central nervous system (CNS). Inhalation of different fragrances can affect immunological reactions in response to an antigen but also may have effects on the CNS and cognitive activity. We performed an exploratory study of the immunomodulatory ability of a series of compounds representing each of the 10 odor categories or clusters described previously. We evaluated the impact of each particular odor on the immune response after immunization with the model antigen ovalbumin in combination with the TLR3 agonist poly I:C. We found that some odors behave as immunostimulatory agents, whereas others might be considered as potential immunosuppressant odors. Interestingly, the immunomodulatory capacity was, in some cases, strain-specific. In particular, one of the fragrances, carvone, was found to be immunostimulatory in BALB/c mice and immunosuppressive in C57BL/6J mice, facilitating or impairing viral clearance, respectively, in a model of a viral infection with a recombinant adenovirus. Importantly, inhalation of the odor improved the memory capacity in BALB/c mice in a fear-conditioning test, while it impaired this same capacity in C57BL/6J mice. The improvement in memory capacity in BALB/c was associated with higher CD3+ T cell infiltration into the hippocampus and increased local expression of mRNA coding for IL-1β, TNF-α, and IL-6 cytokines. In contrast, the memory impairment in C57BL/6 was associated with a reduction in CD3 numbers and an increase in IFN-γ. These data suggest an association between the immunomodulatory capacity of smells and their impact on the cognitive functions of the animals. These results highlight the potential of studying odors as therapeutic agents for CNS-related diseases

Identification of novel therapeutic strategies for Alzheimer’s disease

La Enfermedad de Alzheimer (EA) constituye actualmente la principal forma de demencia en los ancianos afectando a más de 50 millones de personas en todo el mundo. La EA es una enfermedad neurodegenerativa, progresiva e irreversible para la que no existen terapias efectivas, este hecho unido a la alta tasa de fallo obtenida en los ensayos clínicos, pone de manifiesto la urgente necesidad de encontrar nuevas estrategias terapéuticas para esta devastadora enfermedad. Varios autores han sugerido que, teniendo en cuenta el origen multifactorial de la EA, el uso de terapias dirigidas a varias dianas podría ser una estrategia terapéutica prometedora. En este sentido, en la presente tesis, se ha validado la eficacia de una nueva terapia dual, basada en la inhibición simultanea de histona deacetilasa 6 (HDAC6) y fosfodiesterasa 9 (PDE9) para la EA. El tratamiento crónico con CM-695, un novedoso inhibidor dual de HDAC6 y PDE9, ha sido capaz de revertir el déficit cognitivo y de reducir la patología amiloide en el modelo murino de EA Tg2576, un efecto terapéutico mediado, al menos en parte, por un aumento de las chaperonas GRP78 y Hsp70. Por otro lado, se ha empleado una aproximación novedosa basada en el estudio de sujetos resilientes al deterioro cognitivo, para identificar nuevas dianas terapéuticas para la EA. Específicamente, se ha identificado una enzima pobremente caracterizada hasta el momento que parece estar disminuida en EA. Además, se ha demostrado que su sobreexpresión, mediada por vectores adeno-asociados, en el hipocampo de ratones del modelo de EA APP/PS1 revierte el deterioro cognitivo sin afectar la patología amiloide o tau. Así mismo, se ha observado que su sobreexpresión también mejora la retención de memoria en ratones wild-type envejecidos. Por lo tanto, los resultados obtenidos sugieren que la sobreexpresión de esta enzima podría ser una estrategia terapéutica prometedora para la EA y otras enfermedades que cursen con demencia

Amyloid beta mediates memory formation

The amyloid precursor protein (APP) undergoes sequential cleavages to generate various polypeptides, including the amyloid β (1–42) peptide (Aβ[1–42]), which is believed to play a major role in amyloid plaque formation in Alzheimer's disease (AD). Here we provide evidence that, in contrast with its pathological role when accumulated, endogenous Aβ in normal hippocampi mediates learning and memory formation. Furthermore, hippocampal injection of picomolar concentrations of exogenous Aβ(1–42) enhances memory consolidation. Correlative data suggest that Aβ peptides may exert their function via nicotinic acethylcoline receptors. Hence, Aβ peptides, including Aβ(1–42), play an important physiological role in hippocampal memory formation

Phosphodiesterase-5 Inhibitors: Action on the Signaling Pathways of Neuroinflammation, Neurodegeneration, and Cognition

Submitted by Adagilson Silva ([email protected]) on 2017-09-12T18:00:54Z No. of bitstreams: 1 26770022 2015 pei-pho.oa.pdf: 711489 bytes, checksum: 639d778eed18409940028659a76ea9fa (MD5)Approved for entry into archive by Adagilson Silva ([email protected]) on 2017-09-12T19:35:23Z (GMT) No. of bitstreams: 1 26770022 2015 pei-pho.oa.pdf: 711489 bytes, checksum: 639d778eed18409940028659a76ea9fa (MD5)Made available in DSpace on 2017-09-12T19:35:23Z (GMT). No. of bitstreams: 1 26770022 2015 pei-pho.oa.pdf: 711489 bytes, checksum: 639d778eed18409940028659a76ea9fa (MD5) Previous issue date: 2015Fundação Oswaldo Cruz. Instituto Aggeu Magalhães. Recife, PE, BrasilPhosphodiesterase type 5 inhibitors (PDE5-Is) have recently emerged as a potential therapeutic strategy for neuroinflammatory, neurodegenerative, and memory loss diseases. Mechanistically, PDE5-Is produce an anti-inflammatory and neuroprotection effect by increasing expression of nitric oxide synthases and accumulation of cGMP and activating protein kinase G (PKG), the signaling pathway of which is thought to play an important role in the development of several neurodiseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). The aim of this paper was to review present knowledge of the signaling pathways that underlie the use of PDE5-Is in neuroinflammation, neurogenesis, learning, and memory