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The amyloid-[beta] (A[beta] cascade hypothesis of Alzheimer's disease (AD) maintains that accumulation of A[beta] peptide constitutes a critical event in the early disease pathogenesis. The direct binding between A[beta] and apolipoprotein E (apoE) is an important factor implicated in both A[beta] clearance and its deposition in the brain's parenchyma and the walls of meningoencephalic vessels as cerebral amyloid angiopathy. With the aim of testing the effect of blocking the apoE/A[beta] interaction in vivo as a potential novel therapeutic target for AD pharmacotherapy, we have developed A[beta]12-28P, which is a blood-brain-barrier-permeable nontoxic, and nonfibrillogenic synthetic peptide homologous to the apoE binding site on the full-length A[beta]. A[beta]12-28P binds with high affinity to apoE, preventing its binding to A[beta], but has no direct effect on A[beta] aggregation. A[beta]12-28P shows a strong pharmacological effect in vivo. Its systemic administration resulted in a significant reduction of A[beta] plaques and cerebral amyloid angiopathy burden and a reduction of the total brain level of A[beta] in two AD transgenic mice models. The treatment did not affect the levels of soluble A[beta] fraction or A[beta] oligomers, indicating that inhibition of the apoE/A[beta] interaction in vivo has a net effect of increasing A[beta] clearance over deposition and at the same time does not create conditions favoring formation of toxic oligomers. Furthermore, behavioral studies demonstrated that treatment with A[beta]12-28P prevents a memory deficit in transgenic animals. These findings provide evidence of another therapeutic approach for AD. Alzheimer's pathology | memory boss prevention | peptide | transgenic mice | treatment

The present study examined the ability of 6-fluoronorepinephrine (6FNE), a full selective α-adrenoceptor agonist, to produce antidepressant-like effects in mice. The drug, administered in the 4th ventricle, produced marked anti-immobility effects at mid-dose range in the acute forced swim, tail suspension and repeated open-space forced swim tests with minimal effect on open-field motor activity and also reversed anhedonia following lipopolysaccharide administration. Its antidepressant effects were equal to or greater than that of an established systemic antidepressant, desmethylimipramine, given subacutely. Experiments with α-adrenoceptor antagonists indicated that the drug acts primarily via the α2-receptor in contrast to endogenous catecholamines which appear to control depressive behaviour primarily via the α1-receptor. Antidepressant activity declined at higher doses signifying a possible pro-depressant effect of one of the α-adrenoceptor subtypes. Compared to the selective α2-agonist, dexmedetomidine, 6FNE showed equivalent antidepressant action in the tail suspension test but appeared to have a greater efficacy or speed of action in the repeated open-space forced swim test which produces a more sustained depression. Studies of regional brain Fos expression induced during the antidepressant tests showed that 6FNE tended to inhibit neural activity in two stress-responsive regions (locus coeruleus and paraventricular hypothalamus) but to enhance activity in two areas involved in motivated behaviour (nucleus accumbens shell and lateral septal nucleus) producing a neural pattern consistent with antidepressant action. It is concluded that 6FNE elicits a rapid and effective antidepressant and anti-stress response that may compare favourably with available antidepressants. [ABSTRACT FROM AUTHOR]

Harnessing the immune system to clear protein aggregates is emerging as a promising approach to treat various neurodegenerative diseases. In Alzheimer's disease (AD), several clinical trials are ongoing using active and passive immunotherapy targeting the amyloid-p (An) peptide. Limited emphasis has been put into clearing tau/tangle pathology, another major hallmark of the disease. Recent findings from the first A13 vaccination trial suggest that this approach has limited effect on tau pathology and that A plaque clearance may not halt or slow the progression of dementia in individuals with mild-to-moderate AD. To assess within a reasonable timeframe whether targeting tau pathology with immunotherapy could prevent cognitive decline, we developed a new model with accelerated tangle development. It was generated by crossing available strains that express all six human tau isoforms and the M146L preseniin mutation. Here, we show that this unique approach completely prevents severe cognitive impairment in three different tests. This remarkable effect correlated well with extensive clearance of abnormal tau within the brain. Overall, our findings indicate that immunotherapy targeting pathological tau is very feasible for tauopathies, and should be assessed in clinical trials in the near future. [ABSTRACT FROM AUTHOR]

Immunotherapy holds great promise for Alzheimer's disease (AD) and other conformational disorders but certain adverse reactions need to be overcome. Prior to the side effects in the first Elan/Wyeth AD vaccine trial, we proposed using amyloid-beta (Abeta) derivatives as a safer approach. The route of administration may also affect vaccine safety. To assess the feasibility of oral immunization that promotes mucosal immunity, Tg2576 AD model mice were treated prophylactically three times over 6 weeks starting at 3-5 months of age with a Salmonella vaccine expressing K6Abeta(1-30). At 22-24 months of age, cortical Abeta plaque burden and total Abeta(40/42) levels were reduced by 48-75% in the immunized mice compared to controls, which received unmodified Salmonella. Plaque clearance was not associated with increased microglial activation, which may be explained by the long treatment period. Furthermore, cerebral microhemorrhages were not increased in the treated mice in contrast to several passive Abeta antibody studies. These results further support our findings with this immunogen delivered subcutaneously and demonstrate its efficacy when given orally, which may provide added benefits for human use. [ABSTRACT FROM AUTHOR]

α1-Adrenoceptors of the locus coeruleus (LC) have been implicated in behavioral activation in novel surroundings, but the endogenous agonist that activates these receptors has not been established. In addition to the canonical activation of α1-receptors by norepinephrine (NE), there is evidence that dopamine (DA) may also activate certain brain α1-receptors. This study examined the contribution of DA to exploratory activity in a novel cage by determining the effect of infusion of various dopaminergic and adrenergic drugs into the mouse LC. It was found that the D2/D3 agonist, quinpirole, which selectively blocks the release of CNS DA, produced a dose-dependent and virtually complete abolition of exploration and all movement in the novel cage test. The quinpirole-induced inactivity was significantly attenuated by coinfusion of DA but not by the D1 agonist, SKF38390. Furthermore, the DA attenuation of quinpirole inactivity was blocked by coinfusion of the α1-adrenergic receptor antagonist, terazosin, but not by the D1 receptor antagonist, SCH23390. LC infusions of either quinpirole or terazosin also produced profound inactivity in DA-β-hydroxylase knockout (Dbh −/−) mice that lack NE, indicating that their behavioral effects were not due to an alteration of the release or action of LC NE. Measurement of endogenous DA, NE, and 5HT and their metabolites in the LC during exposure to the novel cage indicated an increase in the turnover of DA and NE but not 5HT. These results indicate that DA is a candidate as an endogenous agonist for behaviorally activating LC α1-receptors and may play a role in the activation of this nucleus by novel surroundings. Synapse 62:516-523, 2008. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Immunotherapies for various neurodegenerative diseases have recently emerged as a promising approach for clearing pathological protein conformers in these disorders. This type of treatment has not been assessed in models that develop neuronal tau aggregates as observed in frontotemporal dementia and Alzheimer's disease. Here, we present that active immunization with a phosphorylated tau epitope, in P301L tangle model mice, reduces aggregated tau in the brain and slows progression of the tangle-related behavioral phenotype. Females had more tau pathology than males but were also more receptive to the immunotherapy. The tau antibodies generated in these animals recognized pathological tau on brain sections. Performance on behavioral assays that require extensive motor coordination correlated with tau pathology in corresponding brain areas, and antibody levels against the immunogen correlated inversely with tau pathology. Interestingly, age-dependent autoantibodies that recognized recombinant tau protein but not the immunogen were detected in the P301L mice. To confirm that anti-tau antibodies could enter the brain and bind to pathological tau, FITC-tagged antibodies purified from a P301L mouse, with a high antibody titer against the immunogen, were injected into the carotid artery of P301L mice. These antibodies were subsequently detected within the brain and colocalized with PHF1 and MC1 antibodies that recognize pathological tau. Currently, no treatment is available for clearing tau aggregates. Our present findings may lead to a novel therapy targeting one of the major hallmarks of Alzheimer's disease and frontotemporal dementia. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this experiment was to determine if the low molecular weight heparin (LMWH) enoxaparin could extend the treatment window for thrombolysis in a mouse model of embolic stroke. Methods: To establish the treatment window, mice were treated with tPA 2, 3 or 4 hours after clot insertion. Results showed that only the 2 hour treatment group exhibited infarct volumes significantly smaller than untreated controls. We attempted to widen this window by pre-treating mice with enoxaparin (10 mg/kg, s.c.; n=36) 1 hour before embolization. A control group (n=24) was given a saline injection. The enoxaparin-treated animals were subdivided and treated with tPA either 4 (n=12) or 6 hours (n=12) after clot insertion, while the third group (n=12) was given saline. The saline-pre-treated mice were dived into two groups: one group (n=12) received tPA and the other group (n=12) received saline 4 hours post-stroke. Embolization was confirmed by laser Doppler flowmetry and the effects of the resulting infarcts were evaluated by triphenyltetrazolium chloride staining and by behavioral testing. Results: Results showed large infarcts and impaired sensorimotor coordination in the saline pre-treated animals confirming the narrow treatment window. Enoxaparin pre-treatment produced significantly smaller infarcts and improved motor behavior in groups treated with tPA both 4 and 6 hours after embolization. Neither the 4 nor the 6 hour tPA-treated groups showed evidence of intracerebral hemorrhage or external bleeding. Conclusion: These data indicate that the LMWH enoxaparin can significantly increase the therapeutic time window in a mouse model of embolic stroke. [ABSTRACT FROM AUTHOR]

Abstract: Central α1-adrenoceptors are activated by norepinephrine (NE), epinephrine (EPI) and possibly dopamine (DA), and function in two fundamental and opposed types of behavior: (1) positively motivated exploratory and approach activities, and (2) stress reactions and behavioral inhibition. Brain microinjection studies have revealed that the positive-linked receptors are located in eight to nine brain regions spanning the neuraxis including the secondary motor cortex, piriform cortex, nucleus accumbens, preoptic area, lateral hypothalamic area, vermis cerebellum, locus coeruleus, dorsal raphe and possibly the C1 nucleus of the ventrolateral medulla, whereas the stress-linked receptors are present in at least three areas including the paraventricular nucleus of the hypothalamus, central nucleus of the amygdala and bed nucleus of the stria terminalis. Recent studies utilizing c-fos expression and mitogen-activated protein kinase activation have shown that various diverse models of depression in mice produce decreases in positive region-neural activity elicited by motivating stimuli along with increases in neural activity of stress areas. Both types of change are attenuated by various antidepressant agents. This has suggested that the balance of the two networks determines whether an animal displays depressive behavior. A central unresolved question concerns how the α1-receptors in the positive-activity and stress systems are differentially activated during the appropriate behavioral conditions and to what extent this is related to differences in endogenous ligands or receptor subtype distributions. [Copyright &y& Elsevier]

The present study investigated, by use of fos immunohistochemistry, whether the functional activity of α1-adrenoceptors is elevated during heightened behavioral activity in brain regions shown earlier to contain motoric α1-receptors. In confirmation, marked c-fos responses that were blocked by an α1-antagonist (prazosin) were found in four of these brain regions (secondary motor, cingulate, piriform cortices, and nucleus accumbens) of animals exposed to a mildly novel environment (clean cage), which elicits a high degree of sustained exploratory activity. Experimental restriction of exploratory activity in the novel cage by a small enclosure did not reduce the fos responses in these areas, and in fact, enhanced gene expression when carried out in home-caged animals suggesting that the fos response may be more closely associated with the motivation to be active rather than activity itself. Experiments with locally administered α1-agonists and antagonists in the cortex by reverse dialysis showed that the above mentioned α1-dependent-fos responses were the result of activation of local α1-receptors in these brain regions. Unlike the aforementioned brain regions, the fos response of the locus coeruleus was not blocked by prazosin, and this nucleus also showed a marked fos increase to prazosin itself possibly as a compensatory response to the blockade of forebrain α1-receptors. Synapse 59:299-307, 2006. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]