Clinical repetitive transcranial magnetic stimulation for veterans with major depressive disorder.

BACKGROUND: Repetitive transcranial magnetic stimulation (TMS) is a relatively new treatment modality for patients with major depressive disorder (MDD). Numerous studies have demonstrated the efficacy of TMS for MDD in the general population. However, there is limited information regarding clinical outcomes among veterans receiving TMS for MDD. METHODS: The clinical outcome and characteristics of all veterans with MDD who were treated with TMS as outpatients at the James A. Haley Veterans' Hospital from October 2013 to December 2016 were assessed. RESULTS: Among 40 patients who received TMS, there was a significant improvement of depressive symptoms using the Quick Inventory of Depressive Symptomatology-Self-Report (45% response, 20% remission) and the Montgomery-Åsberg Depression Rating Scale (61.9% response, 42.9% remission). In addition to significant improvement in depressive symptoms, self-report of anxiety symptoms and function significantly improved. TMS was generally well tolerated, with only a small percentage of patients discontinuing treatment due to side effects. No seizures or persistent adverse effects were observed or reported. CONCLUSIONS: TMS is an effective and well-tolerated option for MDD in a veteran population with significant treatment resistance and multiple comorbidities.

Soluble amyloid precursor protein alpha inhibits tau phosphorylation through modulation of GSK3ß signaling pathway.

We recently found that sAPPα decreases amyloid-beta generation by directly associating with ß-site amyloid precursor protein (APP)-converting enzyme 1 (BACE1), thereby modulating APP processing. Because inhibition of BACE1 decreases glycogen synthase kinase 3 beta (GSK3ß)-mediated Alzheimer's disease (AD)-like tau phosphorylation in AD patient-derived neurons, we determined whether sAPPα also reduces GSK3ß-mediated tau phosphorylation. We initially found increased levels of inhibitory phosphorylation of GSK3ß (Ser9) in primary neurons from sAPPα over-expressing mice. Further, recombinant human sAPPα evoked the same phenomenon in SH-SY5Y cells. Further, in SH-SY5Y cells over-expressing BACE1, and HeLa cells over-expressing human tau, sAPPα reduced GSK3ß activity and tau phosphorylation. Importantly, the reductions in GSK3ß activity and tau phosphorylation elicited by sAPPα were prevented by BACE1 but not γ-secretase inhibition. In accord, AD mice over-expressing human sAPPα had less GSK3ß activity and tau phosphorylation compared with controls. These results implicate a direct relationship between APP ß-processing and GSK3ß-mediated tau phosphorylation and further define the central role of sAPPα in APP autoregulation and AD pathogenesis.

Efavirenz promotes ß-secretase expression and increased Aß1-40,42 via oxidative stress and reduced microglial phagocytosis: implications for HIV associated neurocognitive disorders (HAND).

Efavirenz (EFV) is among the most commonly used antiretroviral drugs globally, causes neurological symptoms that interfere with adherence and reduce tolerability, and may have central nervous system (CNS) effects that contribute in part to HIV associated neurocognitive disorders (HAND) in patients on combination antiretroviral therapy (cART). Thus we evaluated a commonly used EFV containing regimen: EFV/zidovudine (AZT)/lamivudine (3TC) in murine N2a cells transfected with the human "Swedish" mutant form of amyloid precursor protein (SweAPP N2a cells) to assess for promotion of amyloid-beta (Aß) production. Treatment with EFV or the EFV containing regimen generated significantly increased soluble amyloid beta (Aß), and promoted increased ß-secretase-1 (BACE-1) expression while 3TC, AZT, or, vehicle control did not significantly alter these endpoints. Further, EFV or the EFV containing regimen promoted significantly more mitochondrial stress in SweAPP N2a cells as compared to 3TC, AZT, or vehicle control. We next tested the EFV containing regimen in Aß - producing Tg2576 mice combined or singly using clinically relevant doses. EFV or the EFV containing regimen promoted significantly more BACE-1 expression and soluble Aß generation while 3TC, AZT, or vehicle control did not. Finally, microglial Aß phagocytosis was significantly reduced by EFV or the EFV containing regimen but not by AZT, 3TC, or vehicle control alone. These data suggest the majority of Aß promoting effects of this cART regimen are dependent upon EFV as it promotes both increased production, and decreased clearance of Aß peptide.

Potential Autoepitope within the Extracellular Region of Contactin-Associated Protein-like 2 in Mice.

AIMS: Implicated in autoimmune encephalitis, neuromyotonia and genetic forms of autism, here we report that contactin-associated protein-like 2 (CNTNAP2) contains a potential autoepitope within the extracellular region. METHODOLOGY: CNTNAP2 sequence-similar regions (CSSRs) from human pathogens were identified. Sera from autistic and control children were obtained and analyzed for the presence of antibodies able to bind CSSRs. One such candidate CSSR was evaluated for evidence of autoimmune responses to CNTNAP2 in a mouse model of acute infection. RESULTS: Autistic and control children sera contained antibodies able to discrete regions of CNTNAP2. In a murine model of acute infection, a CSSR derived from the N-terminal extracellular region of CNTNAP2 resulted in anti-CNTNAP2 antibody production, proinflammatory cytokine elevation, cerebellar and cortical white matter T-cell infiltration as well as motor dysfunction. CONCLUSION: Taken together, these data suggest that CNTNAP2 contains a potential autoepitope within the extracellular region.

Luteolin reduces Alzheimer's disease pathologies induced by traumatic brain injury.

Traumatic brain injury (TBI) occurs in response to an acute insult to the head and is recognized as a major risk factor for Alzheimer's disease (AD). Indeed, recent studies have suggested a pathological overlap between TBI and AD, with both conditions exhibiting amyloid-beta (Aß) deposits, tauopathy, and neuroinflammation. Additional studies involving animal models of AD indicate that some AD-related genotypic determinants may be critical factors enhancing temporal and phenotypic symptoms of TBI. Thus in the present study, we examined sub-acute effects of moderate TBI delivered by a gas-driven shock tube device in Aß depositing Tg2576 mice. Three days later, significant increases in b-amyloid deposition, glycogen synthase-3 (GSK-3) activation, phospho-tau, and pro-inflammatory cytokines were observed. Importantly, peripheral treatment with the naturally occurring flavonoid, luteolin, significantly abolished these accelerated pathologies. This study lays the groundwork for a safe and natural compound that could prevent or treat TBI with minimal or no deleterious side effects in combat personnel and others at risk or who have experienced TBI.

Mycoplasma hyorhinis markedly degrades ß-amyloid peptides in vitro and ex vivo: a novel biological approach for treating Alzheimer's disease?

Accumulation of amyloid-ß (Aß) peptides (predominantly Aß40, 42) and their aggregation into plaques in the brain are thought to be the one of the major causes of Alzheimer's disease (AD). Originally discovered in our Chinese hamster ovary (CHO) cell line stably expressing human wild-type amyloid precursor protein (APP) (CHO/APPwt) cultures devoid of Aß production, we found that Mycoplasma selectively degrades soluble Aß in a time and dose (colony forming unit) dependent manner. Moreover, we fully characterized the Mycoplasma species as Mycoplasma hyorhinis (M. hyorhinis) by genetic and colony morphological analyses by light microscopy. Most interestingly, we attenuated the pathogenicity of M. hyorhinis by γ irradiation (3.5 Gy), and found that its ability to degrade Aß was retained. On the other hand, heated and sonicated M. hyorhinis failed to retain this ability to degrade Aß, suggesting that this degradation requires viable cells and likely a biologically active signaling pathway. In addition, we found that M. hyorhinis can degrade Aß produced in AD model mice (PSAPP mice) ex vivo. Finally, we found that irradiated (non-pathogenic) M. hyorhinis also can degrade Aß produced in PSAPP mice in vivo. These studies suggest that irradiated (non-pathogenic) M. hyorhinis can be a novel and alternative biological strategy for AD treatment.

GFAP expression and social deficits in transgenic mice overexpressing human sAPPα.

Autistic individuals display impaired social interactions and language, and restricted, stereotyped behaviors. Elevated levels of secreted amyloid precursor protein-alpha (sAPPα), the product of α-secretase cleavage of APP, are found in the plasma of some individuals with autism. The sAPPα protein is neurotrophic and neuroprotective and recently showed a correlation to glial differentiation in human neural stem cells (NSCs) via the IL-6 pathway. Considering evidence of gliosis in postmortem autistic brains, we hypothesized that subsets of patients with autism would exhibit elevations in CNS sAPPα and mice generated to mimic this observation would display markers suggestive of gliosis and autism-like behavior. Elevations in sAPPα levels were observed in brains of autistic patients compared to controls. Transgenic mice engineered to overexpress human sAPPα (TgsAPPα mice) displayed hypoactivity, impaired sociability, increased brain glial fibrillary acidic protein (GFAP) expression, and altered Notch1 and IL-6 levels. NSCs isolated from TgsAPPα mice, and those derived from wild-type mice treated with sAPPα, displayed suppressed ß-tubulin III and elevated GFAP expression. These results suggest that elevations in brain sAPPα levels are observed in subsets of individuals with autism and TgsAPPα mice display signs suggestive of gliosis and behavioral impairment.

Baicalein reduces ß-amyloid and promotes nonamyloidogenic amyloid precursor protein processing in an Alzheimer's disease transgenic mouse model.

Baicalein, a flavonoid isolated from the roots of Scutellaria baicalensis, is known to modulate γ-aminobutyric acid (GABA) type A receptors. Given prior reports demonstrating benefits of GABAA modulation for Alzheimer's disease (AD) treatment, we wished to determine whether this agent might be beneficial for AD. CHO cells engineered to overexpress wild-type amyloid precursor protein (APP), primary culture neuronal cells from AD mice (Tg2576) and AD mice were treated with baicalein. In the cell cultures, baicalein significantly reduced the production of ß-amyloid (Aß) by increasing APP α-processing. These effects were blocked by the GABAA antagonist bicuculline. Likewise, AD mice treated daily with i.p. baicalein for 8 weeks showed enhanced APP α-secretase processing, reduced Aß production, and reduced AD-like pathology together with improved cognitive performance. Our findings suggest that baicalein promotes nonamyloidogenic processing of APP, thereby reducing Aß production and improving cognitive performance, by activating GABAA receptors.

Psychotropic effects of antimicrobials and immune modulation by psychotropics: implications for neuroimmune disorders.

Antimicrobial compounds and psychotropic medications often share overlapping mechanisms of actions and pharmacological effects. The immune system appears to be an important site of interaction as several antimicrobials display neurological and, at times, direct psychotropic effects, while psychotropics have shown significant immunomodulatory properties. The isoniazid class of antibiotics for example has been shown to possess monoamine oxidase activity, while selective serotonin reuptake inhibitors have shown significant effects on leukocyte populations. As the importance of the immune system's role in CNS homeostasis and disease continues to move to the forefront of neuropsychiatric research, these shared pharmacological effects may provide an important insight, elucidating the complexities in neuroimmune pathophysiology and guiding the development of potential treatments.

The role of glycogen synthase kinase-3 signaling in neurodevelopment and fragile X syndrome.

Fragile X syndrome (FXS), one of the most common genetic causes of autism, results from a loss of fragile X mental retardation protein (FMRP) expression. At the molecular level, abnormal neurodevelopment is thought to result from dysregulated protein synthesis of key neural synaptic proteins, however recent evidence suggests broader roles for this protein including glutamate signaling, memory, and regulation of the critical serine/threonine regulatory kinase, glycogen synthase kinase-3 (GSK-3). In this review, genetic and molecular features of FXS are detailed in the context of FXS neuropathology. Additionally, potential mechanisms by which FMRP silencing impacts GSK-3 and GSK-3-associated signaling pathways are discussed. As GSK-3 signaling represents a central regulatory node for critical neurodevelopmental pathways, understanding how FXS results from FMRP-mediated GSK-3 dysregulation may provide novel therapeutic targets for disease-modifying interventions for FXS and related ASDs.

The immunology of traumatic brain injury: a prime target for Alzheimer's disease prevention.

A global health problem, traumatic brain injury (TBI) is especially prevalent in the current era of ongoing world military conflicts. Its pathological hallmark is one or more primary injury foci, followed by a spread to initially normal brain areas via cascades of inflammatory cytokines and chemokines resulting in an amplification of the original tissue injury by microglia and other central nervous system immune cells. In some cases this may predispose individuals to later development of Alzheimer's disease (AD). The inflammatory-based progression of TBI has been shown to be active in humans for up to 17 years post TBI. Unfortunately, all neuroprotective drug trials have failed, and specific treatments remain less than efficacious. These poor results might be explained by too much of a scientific focus on neurons without addressing the functions of microglia in the brain, which are at the center of proinflammatory cytokine generation. To address this issue, we provide a survey of the TBI-related brain immunological mechanisms that may promote progression to AD. We discuss these immune and microglia-based inflammatory mechanisms involved in the progression of post-trauma brain damage to AD. Flavonoid-based strategies to oppose the antigen-presenting cell-like inflammatory phenotype of microglia will also be reviewed. The goal is to provide a rationale for investigations of inflammatory response following TBI which may represent a pathological link to AD. In the end, a better understanding of neuroinflammation could open therapeutic avenues for abrogation of secondary cell death and behavioral symptoms that may mediate the progression of TBI to later AD.

Soluble amyloid precursor protein-α modulates ß-secretase activity and amyloid-ß generation.

In sporadic age-related forms of Alzheimer's disease (AD), it is unclear why amyloid-ß (Aß) peptides accumulate. Here we show that soluble amyloid precursor protein-α (sAPP-α) decreases Aß generation by directly associating with ß-site APP-converting enzyme (BACE)1, thereby modulating APP processing. Whereas specifically targeting sAPP-α using antibodies enhances Aß production; in transgenic mice with AD-like pathology, sAPP-α overexpression decreases ß-amyloid plaques and soluble Aß. In support, immunoneutralization of sAPP-α increases APP amyloidogenic processing in these mice. Given our current findings, and because a number of risk factors for sporadic AD serve to lower levels of sAPP-α in brains of AD patients, inadequate sAPP-α levels may be sufficient to polarize APP processing towards the amyloidogenic, Aß-producing route. Therefore, restoration of sAPP-α or enhancement of its association with BACE may be viable strategies to ameliorate imbalances in APP processing that can lead to AD pathogenesis.

Aberrant T-lymphocyte development and function in mice overexpressing human soluble amyloid precursor protein-α: implications for autism.

Abnormalities in T-lymphocyte populations and function are observed in autism. Soluble amyloid precursor protein α (sAPP-α) is elevated in some patients with autism and is known to be produced by immune cells. In light of the well-established role of sAPP-α in proliferation, growth, and survival of neurons, we hypothesized an analogous role in the immune system. Thus, we explored whether sAPP-α could modulate immune development and function, especially aspects of the pinnacle cell of the adaptive arm of the immune system: the T cell. To do this, we generated mice overexpressing human sAPP-α and characterized elements of T-cell development, signal transduction, cytokine production, and innate/adaptive immune functions. Here, we report that transgenic sAPP-α-overexpressing (TgsAPP-α) mice displayed increased proportions of CD8(+) T cells, while effector memory T cells were decreased in the thymus. Overall apoptotic signal transduction was decreased in the thymus, an effect that correlated with dramatic elevations in Notch1 activation; while active-caspase-3/total-caspase-3 and Bax/Bcl-2 ratios were decreased. Greater levels of IFN-γ, IL-2, and IL-4 were observed after ex vivo challenge of TgsAPP-α mouse splenocytes with T-cell mitogen. Finally, after immunization, splenocytes from TgsAPP-α mice displayed decreased levels IFN-γ, IL-2, and IL-4, as well as suppressed ZAP70 activation, after recall antigen stimulation. Given elevated levels of circulating sAPP-α in some patients with autism, sAPP-α could potentially drive aspects of immune dysfunction observed in these patients, including dysregulated T-cell apoptosis, aberrant PI3K/AKT signaling, cytokine alterations, and impaired T-cell recall stimulation.

Autoreactive-Aß antibodies promote APP ß-secretase processing.

Several prior investigations of Alzheimer's disease (AD) patients have indicated naturally occurring autoantibodies against amyloid-ß (Aß) species are produced. Although many studies have focused on the relative concentrations or binding affinities of autoantibodies against Aß-related proteins in AD and aging, data regarding their functional properties are limited. It is generally believed that these antibodies act to aid in clearance of Aß. However, as antibodies which bind to Aß also typically bind to the parent amyloid precursor protein (APP), we reasoned that certain Aß-targeting autoantibodies may bind to APP thereby altering its conformation and processing. Here we show for the first time, that naturally occurring Aß-reactive autoantibodies isolated from AD patients, but not from healthy controls, promote ß-secretase activity in cultured cells. Furthermore, using monoclonal antibodies to various regions of Aß, we found that antibodies generated against the N-terminal region, especially Aß(1-17) , dose dependently promoted amyloidogenic processing of APP viaß-secretase activation. Thus, this property of certain autoantibodies in driving Aß generation could be of etiological importance in the development of sporadic forms of AD. Furthermore, future passive or active anti-Aß immunotherapies must consider potential off-target effects resulting from antibodies targeting the N-terminus of Aß, as co-binding to the corresponding region of APP may actually enhance Aß generation.

Memantine and catatonia: a case report and literature review.

Catatonia is a movement disorder with various possible etiologies. The majority of cases are associated with an underlying mood or psychotic disorder, while others are caused by medical conditions. Currently, benzodiazepines are the first-line psychopharmacologic agents in the treatment of catatonia. However, several cases have been reported in which treatment with memantine proved to be effective. We present the case of a 92-year-old female with major depressive disorder and associated catatonic symptoms. In this case, the patient's symptoms remitted quickly after the initiation of memantine. We review the possible causes of catatonia and pharmacologic treatments for the condition and highlight the possible benefits of N-methylD-aspartic acid receptor antagonists such as memantine in the treatment of catatonia.

Antiretroviral medications disrupt microglial phagocytosis of ß-amyloid and increase its production by neurons: implications for HIV-associated neurocognitive disorders.

Up to 50% of long-term HIV infected patients, including those with systemically well-controlled infection, commonly experience memory problems and slowness, difficulties in concentration, planning, and multitasking. Deposition of Aß plaques is also a common pathological feature of HIV infection. However, it is not clear whether this accumulation is due to AD-like processes, HIV-associated immunosuppression, Tat protein-induced Aß elevations, and/or the effects of single highly active antiretroviral therapy (ART). Here we evaluated the effects of several ART medications (Zidovudine, Lamivudine, Indinavir, and Abacavir) alone and in combination on: 1) Aß1-40, 42 generation in murine N2a cells transfected with the human "Swedish" mutant form of APP; 2) microglial phagocytosis of FITC-Aß1-42 peptides in cultured murine N9 microglia. We report for the first time that these antiretroviral compounds (10 µM) generally increase Aß generation (~50-200%) in SweAPP N2a cells and markedly inhibit microglial phagocytosis of FITC-Aß1-42 peptides in murine microglia. The most significant amyloidogenic effects were observed with combined ART (p < 0.05); suggesting certain ART medications may have additive amyloidogenic effects when combined. As these antiretroviral compounds are capable of penetrating the blood brain barrier and reaching the concentrations employed in the in vitro studies, these findings raise the possibility that ART may play a casual role in the elevated Aß found in the brains of those infected with HIV. Therefore these compounds may consequently contribute to cognitive decline observed in HIV associated neurocognitive disorders (HAND).

CD45 deficiency drives amyloid-ß peptide oligomers and neuronal loss in Alzheimer's disease mice.

Converging lines of evidence indicate dysregulation of the key immunoregulatory molecule CD45 (also known as leukocyte common antigen) in Alzheimer's disease (AD). We report that transgenic mice overproducing amyloid-ß peptide (Aß) but deficient in CD45 (PSAPP/CD45(-/-) mice) faithfully recapitulate AD neuropathology. Specifically, we find increased abundance of cerebral intracellular and extracellular soluble oligomeric and insoluble Aß, decreased plasma soluble Aß, increased abundance of microglial neurotoxic cytokines tumor necrosis factor-α and interleukin-1ß, and neuronal loss in PSAPP/CD45(-/-) mice compared with CD45-sufficient PSAPP littermates (bearing mutant human amyloid precursor protein and mutant human presenilin-1 transgenes). After CD45 ablation, in vitro and in vivo studies demonstrate an anti-Aß phagocytic but proinflammatory microglial phenotype. This form of microglial activation occurs with elevated Aß oligomers and neural injury and loss as determined by decreased ratio of anti-apoptotic Bcl-xL to proapoptotic Bax, increased activated caspase-3, mitochondrial dysfunction, and loss of cortical neurons in PSAPP/CD45(-/-) mice. These data show that deficiency in CD45 activity leads to brain accumulation of neurotoxic Aß oligomers and validate CD45-mediated microglial clearance of oligomeric Aß as a novel AD therapeutic target.

Flipping the switches: CD40 and CD45 modulation of microglial activation states in HIV associated dementia (HAD).

Microglial dysfunction is associated with the pathogenesis and progression of a number of neurodegenerative disorders including HIV associated dementia (HAD). HIV promotion of an M1 antigen presenting cell (APC) - like microglial phenotype, through the promotion of CD40 activity, may impair endogenous mechanisms important for amyloid- beta (Aß) protein clearance. Further, a chronic pro-inflammatory cycle is established in this manner. CD45 is a protein tyrosine phosphatase receptor which negatively regulates CD40L-CD40-induced microglial M1 activation; an effect leading to the promotion of an M2 phenotype better suited to phagocytose and clear Aß. Moreover, this CD45 mediated activation state appears to dampen harmful cytokine production. As such, this property of microglial CD45 as a regulatory "off switch" for a CD40-promoted M1, APC-type microglia activation phenotype may represent a critical therapeutic target for the prevention and treatment of neurodegeneration, as well as microglial dysfunction, found in patients with HAD.

Mutant presenilin-1 deregulated peripheral immunity exacerbates Alzheimer-like pathology.

Mutations in the presenilin-1 (PS1) gene are independent causes of familial Alzheimer's disease (AD). AD patients have dysregulated immunity, and PS1 mutant mice exhibit abnormal systemic immune responses. To test whether immune function abnormality caused by a mutant human PS1 gene (mhPS1) could modify AD-like pathology, we reconstituted immune systems of AD model mice carrying a mutant human amyloid precursor protein gene (mhAPP; Tg2576 mice) or both mhAPP and mhPS1 genes (PSAPP mice) with allogeneic bone marrow cells. Here, we report a marked reduction in amyloid-ß (Aß) levels, ß-amyloid plaques and brain inflammatory responses in PSAPP mice following strain-matched wild-type PS1 bone marrow reconstitution. These effects occurred with immune switching from pro-inflammatory T helper (Th) 1 to anti-inflammatory Th2 immune responses in the periphery and in the brain, which likely instructed microglia to phagocytose and clear Aß in an ex vivo assay. Conversely, Tg2576 mice displayed accelerated AD-like pathology when reconstituted with mhPS1 bone marrow. These data show that haematopoietic cells bearing the mhPS1 transgene exacerbate AD-like pathology, suggesting a novel therapeutic strategy for AD based on targeting PS1 in peripheral immune cells.