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A PreCISe therapy for vascular dementia: Vascular contributions to cognitive impairment and dementia (VCID) are conditions arising from vascular diseases or abnormalities that result in cognitive impairments. Unfortunately, the pathophysiology of VCID remains to be elucidated. Now, Qiu et al. used samples from patients with vascular dementia and mouse models to show that cis P-tau was increased in the brain and played a major role in causing cognitive impairments in mice. A cis-specific immunotherapy had therapeutic effects in the rodent models of VCID, whereas soluble cis P-tau administration caused neurodegeneration and brain dysfunction resembling VCID. The results suggest that targeting cis P-tau could reduce memory loss and neurodegeneration in VCID. Compelling evidence supports vascular contributions to cognitive impairment and dementia (VCID) including Alzheimer's disease (AD), but the underlying pathogenic mechanisms and treatments are not fully understood. Cis P-tau is an early driver of neurodegeneration resulting from traumatic brain injury, but its role in VCID remains unclear. Here, we found robust cis P-tau despite no tau tangles in patients with VCID and in mice modeling key aspects of clinical VCID, likely because of the inhibition of its isomerase Pin1 by DAPK1. Elimination of cis P-tau in VCID mice using cis-targeted immunotherapy, brain-specific Pin1 overexpression, or DAPK1 knockout effectively rescues VCID-like neurodegeneration and cognitive impairment in executive function. Cis mAb also prevents and ameliorates progression of AD-like neurodegeneration and memory loss in mice. Furthermore, single-cell RNA sequencing revealed that young VCID mice display diverse cortical cell type–specific transcriptomic changes resembling old patients with AD, and the vast majority of these global changes were recovered by cis-targeted immunotherapy. Moreover, purified soluble cis P-tau was sufficient to induce progressive neurodegeneration and brain dysfunction by causing axonopathy and conserved transcriptomic signature found in VCID mice and patients with AD with early pathology. Thus, cis P-tau might play a major role in mediating VCID and AD, and antibody targeting it may be useful for early diagnosis, prevention, and treatment of cognitive impairment and dementia after neurovascular insults and in AD. [ABSTRACT FROM AUTHOR]

The article presents a study which shows the important role of complement C3 or downstream complement activation fragments in plaque pathology, glial responses to plaques, and neuronal dysfunction in the brains of APP/PS1 mice. The significance of complement cascade in microglia-mediated synaptic refinement during brain development is mentioned. The reduction of several proinflammatory cytokines in the brain in APP/PS1 is cited.

The complement system is part of the innate immune response responsible for removing pathogens and cellular debris, in addition to helping to refine CNS neuronal connections via microglia-mediated pruning of inappropriate synapses during brain development. However, less is known about the role of complement during normal aging. Here, we studied the role of the central complement component, C3, in synaptic health and aging. We examined behavior as well as electrophysiological, synaptic, and neuronal changes in the brains of C3-deficient male mice (C3 KO) compared with age-, strain-, and gender-matched C57BL/6J (wild-type, WT) control mice at postnatal day 30, 4 months, and 16 months of age. We found the following: (1) region-specific and age-dependent synapse loss in aged WT mice that was not observed in C3 KO mice; (2) age-dependent neuron loss in hippocampal CA3 (but not in CA1) that followed synapse loss in aged WT mice, neither of which were observed in aged C3 KO mice; and (3) significantly enhanced LTP and cognition and less anxiety in aged C3 KO mice compared with aged WT mice. Importantly, CA3 synaptic puncta were similar between WT and C3 KO mice at P30. Together, our results suggest a novel and prominent role for complement protein C3 in mediating aged-related and region-specific changes in synaptic function and plasticity in the aging brain. [ABSTRACT FROM AUTHOR]

Rationale: Nicotinic acetylcholine receptor (nAChR) agonists, partial agonists, and antagonists have antidepressant-like effects in rodents and reduce symptoms of depression in humans. Objectives: The study determined whether the antidepressant-like effect of the nAChR β2* partial agonist sazetidine-A (sazetidine) in the forced swim test was due to activation or desensitization of β2* nAChRs. The study also determined if sazetidine's behavioral responses in the forced swim test corresponded to β2* nAChRs receptor occupancy and drug bioavailability. Results: Acute antidepressant-like effects in the forced swim test were seen with sazetidine and the full β2* agonist 5-I-A8350 (BALB/cJ mice) and the less selective β2* partial agonist varenicline in C57BL/6J but not BALB/cJ mice. The role of β2* nAChRs was confirmed by results showing: (1) reversal of sazetidine's antidepressant-like effects in the forced swim test by nAChR antagonists mecamylamine and dihydro-β-erythroidine; (2) absence of sazetidine's effect in mice lacking the β2 subunit of the nAChR; and (3) a high correspondence between behaviorally active doses of sazetidine and β2* receptor occupancy. β2* receptor occupancy following acute sazetidine, varenicline, and 5-I-A8350 lasted beyond the duration of action in the forced swim test. Sazetidine's long lasting receptor occupancy did not diminish behavioral efficacy in the forced swim test following repeated dosing. Conclusions: Results demonstrate that activation of a small population of β2* nAChRs (10-40%) is sufficient to elicit sazetidine's antidepressant-like actions without producing tolerance and suggest that ligands that activate β2* nAChRs would be promising targets for the development of a new class of antidepressant. [ABSTRACT FROM AUTHOR]

Abstract: Smoking appears to increase overall levels of stress, despite self-reports that men and women smoke to control symptoms of anxiety. The overall incidence of anxiety disorders is also significantly higher in women. This study examined whether behavioral sensitivity to chronic nicotine varies across sexes in mice. Male and female C57BL/6J mice were exposed chronically to nicotine in the drinking water (50, 100, or 200μg/ml) and tested for locomotor activation and anxiety-like behavior in the elevated plus maze (EPM). Female mice were less sensitive to the locomotor activating effects of chronic nicotine. Whereas both males and females showed increases in locomotor activity at the highest (200μg/ml) concentration of nicotine, only males showed locomotor activation at the middle (100μg/ml) concentration. The decreased sensitivity in females could not be explained by reduced nicotine intake compared to males. In the EPM, nicotine produced an anxiogenic-like response in females, but had no effect in males. Treatment with the high (200μg/ml) dose of nicotine reduced the amount of time spent in the open arms of the EPM in female, but not male mice. No differences in the anxiogenic-like response to chronic nicotine was observed between β2-subunit knockout and wildtype mice, suggesting that β2-subunit containing nicotinic receptors do not mediate the anxiogenic-like response to chronic nicotine in females. This shows that female mice have an anxiogenic-like response to chronic nicotine, but are less sensitive to nicotine''s psychostimulant properties, which may be related to the increased relapse to smoking following abstinence in women. [Copyright &y& Elsevier]

Chronic cocaine produces changes in the dopamine (DA)/D1/cAMP/protein kinase A (PKA)-regulated signaling pathway that may underlie the development of addiction. Given sex differences in the progression to cocaine addiction, we examined the possibility that the PKA pathway is differentially activated by cocaine in male and female rats. Rats were given 24-h access to cocaine (1.5 mg/kg) or saline for 7 days under a discrete trial procedure (four trials per hour). Rats were then retested on responding for cocaine under a progressive-ratio schedule after either 0 (no-delay retest) or 10 (10-day-delay retest) days of abstinence. Markers of PKA-regulated signaling in the striatum and nucleus accumbens were evaluated by Western blotting, including phosphorylation of DA and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at Thr 34 and glutamate receptor 1 (GluR1) at Ser 845. Compared to males, females had higher levels of DARPP-32 phosphorylated at the PKA site in the striatum. Increased phosphorylation of DARPP-32 at the PKA site was also seen in the nucleus accumbens of females compared to males, particularly among controls and rats tested after a 10-day abstinence period. DARPP-32 phosphorylation was also increased as a consequence of cocaine when tested after a 0-day abstinence period in male rats but not female rats. These findings indicate sex differences in PKA-regulated signaling in drug-naïve controls. Furthermore, these data suggest that regulation of PKA signaling by cocaine is differentially influenced in male and female rats as a consequence of cocaine exposure and cocaine abstinence period. [ABSTRACT FROM AUTHOR]

Pyroglutamate-3 amyloid-beta (pGlu-3 Aβ) is an N-terminally truncated Aβ isoform likely playing a decisive role in Alzheimer's disease pathogenesis. Here, we describe a prophylactic passive immunization study in APPswe/PS1ΔE9 mice using a novel pGlu-3 Aβ immunoglobulin G1 (IgG1) monoclonal antibody, 07/1 (150 and 500 μg, intraperitoneal, weekly) and compare its efficacy with a general Aβ IgG1 monoclonal antibody, 3A1 (200 μg, intraperitoneal, weekly) as a positive control. After 28 weeks of treatment, plaque burden was reduced and cognitive performance of 07/1-immunized Tg mice, especially at the higher dose, was normalized to wild-type levels in 2 hippocampal-dependent tests and partially spared compared with phosphate-buffered saline–treated Tg mice. Mice that received 3A1 had reduced plaque burden but showed no cognitive benefit. In contrast with 3A1, treatment with 07/1 did not increase the concentration of Aβ in plasma, suggesting different modes of Aβ plaque clearance. In conclusion, early selective targeting of pGlu-3 Aβ by immunotherapy may be effective in lowering cerebral Aβ plaque burden and preventing cognitive decline in the clinical setting. Targeting this pathologically modified form of Aβ thereby is unlikely to interfere with potential physiologic function(s) of Aβ that have been proposed. [ABSTRACT FROM AUTHOR]

Abstract: The present studies assessed the potential abuse liability and likely mechanism(s) of action of the wake-promoting agent modafinil. Methods: Experiments assessed the locomotor sensitization (LS) and discriminative stimulus (DS) properties of modafinil in mouse and rat, respectively. Comparative data were generated with a range of psychostimulants and monoamine reuptake inhibitors. Results: Repeated administration of d-amphetamine and cocaine, psychostimulants with high abuse liability, resulted in the induction and expression of LS in mice. Bupropion and caffeine, two psychostimulants not abused in humans, were not associated with LS. GBR12909 induced LS during repeated exposure, but there was no evidence of expression of LS after acute challenge following withdrawal. In contrast, repeated administration of modafinil resulted in the expression, but not induction, of LS. d-amphetamine, but not the μ-opioid agonist morphine or the nAChR agonist nicotine, fully substituted for the cocaine DS in rats. The selective dopamine transporter (DAT) inhibitor GBR12909 fully substituted, the preferential norepinephrine transporter (NET) inhibitor desipramine partially substituted, and the selective serotonin reuptake inhibitor citalopram failed to substitute for cocaine. Modafinil fully substituted for cocaine, similar to the mixed DAT/NET inhibitor bupropion. Conclusions: Two preclinical assays indicated potential abuse liability of modafinil; drug discrimination studies suggest DAT blockade by modafinil is a likely mechanism of action in vivo. [Copyright &y& Elsevier]