Effects of Nordic walking in Alzheimer's disease: A single-blind randomized controlled clinical trial.

Non-pharmacological approaches, including exercise programs, have been proposed to improve cognitive function and behavioral symptoms, such as depression, agitation, or aggression, in the management of patients with Alzheimer's disease (AD). Indeed, physical inactivity is one of the main modifiable risk factors in patients with AD, as well as in the development of cardiovascular diseases and related pathologies. Although Nordic Walking (NW), a particular type of aerobic exercise, is known to benefit the health of aging populations, there is little evidence that patients with AD may benefit from this non-pharmacological treatment. In this context, we performed a pilot study in 30 patients with mild/moderate AD to evaluate whether NW influences different cognitive domains, including executive functions, visual-spatial abilities, and verbal episodic memory. To this aim, 15 patients (Control group, CG) underwent reality orientation therapy, music therapy, motor, proprioceptive and postural rehabilitation, and 15 patients (experimental group, EG) in addition to the activities performed by the CG also had the NW with a frequency of twice a week. Neuropsychological assessments and evaluations of daily activities and quality of life were performed at baseline and after 24 weeks. Twenty-two patients, including 13 in the CG and nine in the EG completed the activity program after 24 weeks. The EG showed a significant improvement in the Frontal Assessment Battery, Rey's auditory Verbal Learning Test Delayed Recall, Raven's Colored Progressive Matrices, and completion time for the Stroop Word-Color Interference test, compared to the CG. NW was able to improve cognitive domains like visual-spatial reasoning abilities, verbal episodic memory, selective attention, and processing speed in AD patients. These results, if confirmed by further studies with a larger number of patients and a longer training period, may prospect NW as a safe and likely useful strategy to slow down cognitive impairment in mild/moderate AD.

Low molecular weight, non-peptidic agonists of TrkA receptor with NGF-mimetic activity.

Exploitation of the biologic activity of neurotrophins is desirable for medical purposes, but their protein nature intrinsically bears adverse pharmacokinetic properties. Here, we report synthesis and biologic characterization of a novel class of low molecular weight, non-peptidic compounds with NGF (nerve growth factor)-mimetic properties. MT2, a representative compound, bound to Trk (tropomyosin kinase receptor)A chain on NGF-sensitive cells, as well as in cell-free assays, at nanomolar concentrations and induced TrkA autophosphorylation and receptor-mediated internalization. MT2 binding involved at least two amino-acid residues within TrkA molecule. Like NGF, MT2 increased phosphorylation of extracellular signal-regulated kinase 1/2 and Akt proteins and production of MKP-1 phosphatase (dual specificity phosphatase 1), modulated p38 mitogen-activated protein kinase activation,sustained survival of serum-starved PC12 or RDG cells, and promoted their differentiation. However, the intensity of such responses was heterogenous, as the ability of maintaining survival was equally possessed by NGF and MT2, whereas the induction of differentiation was expressed at definitely lower levels by the mimetic. Analysis of TrkA autophosphorylation patterns induced by MT2 revealed a strong tyrosine (Tyr)490 and a limited Tyr785 and Tyr674/675 activation, findings coherent with the observed functional divarication. Consistently, in an NGF-deprived rat hippocampal neuronal model of Alzheimer Disease, MT2 could correct the biochemical abnormalities and sustain cell survival. Thus, NGF mimetics may reveal interesting investigational tools in neurobiology, as well as promising drug candidates.

Low molecular weight, non-peptidic agonists of TrkA receptor with NGF-mimetic activity.

Exploitation of the biologic activity of neurotrophins is desirable for medical purposes, but their protein nature intrinsically bears adverse pharmacokinetic properties. Here, we report synthesis and biologic characterization of a novel class of low molecular weight, non-peptidic compounds with NGF (nerve growth factor)-mimetic properties. MT2, a representative compound, bound to Trk (tropomyosin kinase receptor)A chain on NGF-sensitive cells, as well as in cell-free assays, at nanomolar concentrations and induced TrkA autophosphorylation and receptor-mediated internalization. MT2 binding involved at least two amino-acid residues within TrkA molecule. Like NGF, MT2 increased phosphorylation of extracellular signal-regulated kinase1/2 and Akt proteins and production of MKP-1 phosphatase (dual specificity phosphatase 1), modulated p38 mitogen-activated protein kinase activation, sustained survival of serum-starved PC12 or RDG cells, and promoted their differentiation. However, the intensity of such responses was heterogenous, as the ability of maintaining survival was equally possessed by NGF and MT2, whereas the induction of differentiation was expressed at definitely lower levels by the mimetic. Analysis of TrkA autophosphorylation patterns induced by MT2 revealed a strong tyrosine (Tyr)490 and a limited Tyr785 and Tyr674/675 activation, findings coherent with the observed functional divarication. Consistently, in an NGF-deprived rat hippocampal neuronal model of Alzheimer Disease, MT2 could correct the biochemical abnormalities and sustain cell survival. Thus, NGF mimetics may reveal interesting investigational tools in neurobiology, as well as promising drug candidates.

Substance P activates ADAM9 mRNA expression and induces α-secretase-mediated amyloid precursor protein cleavage.

Altered levels of Substance P (SP), a neuropeptide endowed with neuroprotective and anti-apoptotic properties, were found in brain areas and spinal fluid of Alzheimer's disease (AD) patients. One of the hallmarks of AD is the abnormal extracellular deposition of neurotoxic beta amyloid (Aß) peptides, derived from the proteolytic processing of amyloid precursor protein (APP). In the present study, we confirmed, the neurotrophic action of SP in cultured rat cerebellar granule cells (CGCs) and investigated its effects on APP metabolism. Incubation with low (5 mM) potassium induced apoptotic cell death of CGCs and amyloidogenic processing of APP, whereas treatment with SP (200 nM) reverted these effects via NK1 receptors. The non-amyloidogenic effect of SP consisted of reduction of Aß(1-42), increase of sAPPα and enhanced α-secretase activity, without a significant change in steady-state levels of cellular APP. The intracellular mechanisms whereby SP alters APP metabolism were further investigated by measuring mRNA and/or steady-state protein levels of key enzymes involved with α-, ß- and γ-secretase activity. Among them, Adam9, both at the mRNA and protein level, was the only enzyme to be significantly down-regulated following the induction of apoptosis (K5) and up-regulated after SP treatment. In addition to its neuroprotective properties, this study shows that SP is able to stimulate non-amyloidogenic APP processing, thereby reducing the possibility of generation of toxic Aß peptides in brain.

Does the term 'trophic' actually mean anti-amyloidogenic? The case of NGF.

The term trophic is widely used to indicate a general pro-survival action exerted on target cells by different classes of extracellular messengers, including neurotrophins (NTs), a family of low-molecular-weight proteins whose archetypal member is the nerve growth factor (NGF). The pro-survival action exerted by NTs results from a coordinated activation of multiple metabolic pathways, some of which have only recently come to light. NGF has been shown to exert a number of different, experimentally distinguishable effects on neurons, such as survival, differentiation of target neurons, growth of nerve fibers and their guidance (tropism) toward the source of its production. We have proposed a more complete definition of the NGF trophic action that should also include its newly discovered property of inhibiting the amyloidogenic processing of amyloid precursor protein (APP), which is among the first hypothesized primary trigger of Alzheimer's disease (AD) pathogenesis. This inhibitory action appears to be mediated by a complex series of molecular events and by interactions among NGF receptors (TrkA and p75), APP processing and tau metabolic fate and function.

Nerve growth factor as a paradigm of neurotrophins related to Alzheimer's disease.

Converging lines of evidence on the possible connection between NGF signaling and Alzheimer's diseases (AD) are unraveling new facets which could depict this neurotrophin (NTF) in a more central role. AD animal models have provided evidence that a shortage of NGF supply may induce an AD-like syndrome. In vitro experiments, moreover, are delineating a possible temporal and causal link between APP amiloydogenic processing and altered post-translational tau modifications. After NGF signaling interruption, the pivotal upstream players of the amyloid cascade (APP, beta-secretase, and active form of gamma-secretase) are up-regulated, leading to an increased production of amyloid beta peptide (Abeta) and to its intracellular aggregation in molecular species of different sizes. Contextually, the Abeta released pool generates an autocrine toxic loop in the same healthy neurons. At the same time tau protein undergoes anomalous, GSKbeta-mediated, phosphorylation at specific pathogenetic sites (Ser262 and Thr 231), caspase(s) and calpain- I- mediated truncation, detachment from microtubules with consequent cytoskeleton collapse and axonal transport impairment. All these events are inhibited when the amyloidogenic processing is reduced by beta and gamma secretase inhibitors or anti-Abeta antibodies and appear to be causally correlated to TrkA, p75CTF, Abeta, and PS1 molecular association in an Abeta-mediated fashion. In this scenario, the so-called trophic action exerted by NGF (and possibly also by other neurotrophins) in these targets neurons is actually the result of an anti-amyloidogenic activity.

Apoptosis and in vitro Alzheimer disease neuronal models.

Alzheimer disease (AD) is a human neurodegenerative disease characterized by co-existence of extracellular senile plaques (SP) and neurofibrillary tangles (NFT) associated with an extensive neuronal loss, primarily in the cerebral cortex and hippocampus. Several studies suggest that caspase(s)-mediated neuronal death occurs in cellular and animal AD models as well as in human brains of affected patients, although an etiologic role of apoptosis in such neurodegenerative disorder is still debated. This review summarizes the experimental evidences corroborating the possible involvement of apoptosis in AD pathogenesis and discusses the usefulness of ad hoc devised in vitro approaches to study how caspase(s), amyloidogenic processing and tau metabolism might reciprocally interact leading to neuronal death.

Tyrosine kinase nerve growth factor receptor switches from prosurvival to proapoptotic activity via Abeta-mediated phosphorylation.

The present study shows that increased Abeta production in hippocampal neurons, due to a failure of NGF signal, induces an unexpected phosphorylation of tyrosine kinase receptor A (TrkA), followed by activation of the phospholipase C gamma (PLCgamma) pathway and neuronal death. Such phosphorylation seems causally connected with 2 kinases known be involved in amyloidogenesis, Src and CDK5, and associated with alpha and gamma secretase-mediated p75 processing. Pharmacologic inhibition of TrkA phosphorylation and partial silencing of TrkA and/or p75 receptors prevent PLCgamma activation and protect neurons from death. Concomitantly with these events, TrkA, p75, Abeta peptides, and PS1 protein coimmunoprecipitate, suggesting their direct interplay in the subsequent onset of apoptotic death. Together, these findings depict a cellular mechanism whereby the same cellular transducing system may invert its intracellular message from trophic and antiapoptotic to a death signaling, which could also have relevance in the onset of Alzheimer's disease.

HIF-1alpha reveals a binding activity to the promoter of iNOS gene after permanent middle cerebral artery occlusion.

Hypoxia inducible factor (HIF-1)-1alpha is a specific, oxygen-sensitive protein that regulates the activity of HIF-1, a transcriptional factor that increases after cerebral ischemia and may either promote or prevent neuronal survival. In this study to determine whether the inducible nitric oxide synthase (iNOS) gene containing the sequence of the hypoxia-responsive enhancer (HRE) was an HIF-1 target after cerebral ischemia induced by permanent middle cerebral artery occlusion (pMCAO), electrophoretic mobility shift assay (EMSA) and iNOS western blot analysis were performed in the ischemic core, in the area surrounding the infarct and in the hippocampus ipsilateral and contralateral to the lesion. In addition, both HIF-1alpha mRNA and protein expression were examined in the ischemic core, in the area surrounding the ischemic core and in the hippocampus ipsilateral to the insult. Our results revealed that pMCAO up-regulates iNOS protein in the ischemic core, in the area surrounding the ischemic core and in the hippocampus ipsilateral to the lesion, and that the activation of iNOS expression is mediated by HIF-1. Moreover, HIF-1alpha mRNA and protein levels increased in the ischemic core and in the hippocampus ipsilateral to the lesion compared with the levels obtained in the corresponding areas of sham-operated controls or in the contralateral hemisphere. Particularly in the area surrounding the ischemic core, HIF-1alpha protein accumulated during pMCAO although mRNA did not increase. Our study suggests that the activation of HIF-1 might be involved in the mechanisms whereby iNOS promotes cell survival and/or death after cerebral ischemia.

Expression and function of somatostatin receptor subtype 1 in human growth hormone secreting pituitary tumors deriving from patients partially responsive or resistant to long-term treatment with somatostatin analogs.

The role of somatostatin (SS) receptor subtype 1 (SSTR(1)) in mediating the inhibitory effect of SS on growth hormone (GH) secreting pituitary tumors has been recently demonstrated. In the present study, we evaluated the effect of the selective SSTR(1) agonist BIM-23745 on in vitro GH secretion in GH-secreting pituitary tumor cells, deriving from patients resistant or partially responsive to octreotide long-acting release (octreotide-LAR) or lanreotide therapy in vivo and expressing SSTR(1) mRNA. In addition, the inhibiting effect of BIM-23745 on the GH secretion was compared with that of octreotide. Our data demonstrate that (1) SSTR(1) receptor was present in 56.25% (9/16) of the GH-secreting adenomas examined; (2) in all GH-secreting pituitary tumors that expressed SSTR(1), BIM-23745 significantly inhibited GH secretion in vitro, and (3) when SSTR(1) subtype was present in tumors from patients resistant to octreotide-LAR or lanreotide therapy, BIM-23745 was able to inhibit the in vitro GH secretion. In conclusion, the results of the current study suggest that SS analogs selective for the SSTR(1) may represent a further useful approach for the treatment of acromegaly in patients resistant or partially responsive to octreotide-LAR or lanreotide treatment in vivo.

Scleroderma renal crisis analysis of prevalence and outcome in a large italian series.

During a 30-year period, 323 SSc patients were admitted to a tertiary center specialized in connective tissue diseases. Among them 13 (4|X%) developed scleroderma renal crisis (SRC). These 13 SRC patients with respect to the remaining SSc patients were older, were more often affected by diffuse cutaneous systemic sclerosis (dcSSc), and had slightly higher blood pressure and more frequent heart involvement at initial presentation. Among the 13 SRC patients, an older age, a shorter disease duration, and a higher peak serum creatinine correlated with a poor outcome.SRC in Italian patients showed a lower prevalence (4|X%) than in many earlier reports. Mean survival in SRC patients was 6 years. This tended to be less than the 16.5 years for all others, but this trend was not statistically significant at least for those admitted in the post-captopril era.From a clinical point of view, the higher prevalence of later SRC in dcSSc patients presenting with mild arterial hypertension and or heart involvement is worth noting. Many patients were asymptomatic and were detected only on a routine visit. Such patients must be carefully followed to detect any early finding of SRC.