The many "Neurofaces" of Prohibitins 1 and 2: Crucial for the healthy brain, dysregulated in numerous brain disorders.

Prohibitin 1 (PHB1) and prohibitin 2 (PHB2) are proteins that are nearly ubiquitously expressed. They are localized in mitochondria, cytosol and cell nuclei. In the healthy CNS, they occur in neurons and non-neuronal cells (oligodendrocytes, astrocytes, microglia, and endothelial cells) and fulfill pivotal functions in brain development and aging, the regulation of brain metabolism, maintenance of structural integrity, synapse formation, aminoacidergic neurotransmission and, probably, regulation of brain action of certain hypothalamic-pituitary hormones.With regard to the diseased brain there is increasing evidence that prohibitins are prominently involved in numerous major diseases of the CNS, which are summarized and discussed in the present review (brain tumors, neurotropic viruses, Alzheimer disease, Down syndrome, Fronto-temporal and vascular dementia, dementia with Lewy bodies, Parkinson disease, Huntington disease, Multiple sclerosis, Amyotrophic lateral sclerosis, stroke, alcohol use disorder, schizophrenia and autism). Unfortunately, there is no PHB-targeted therapy available for any of these diseases.

Reduced anterior insular cortex volume in male heroin addicts: a postmortem study.

We and others have observed reduced volumes of brain regions, including the nucleus accumbens, globus pallidus, hypothalamus, and habenula in opioid addiction. Notably, the insular cortex has been under increasing study in addiction, and a smaller anterior insula has been found in alcohol-addicted cases. Here, we have investigated whether similar effects occur in heroin addicts compared to healthy controls. Volumes of the anterior and posterior insula in heroin addicts (n = 14) and controls (n = 13) were assessed by morphometry of Nissl-myelin-stained serial whole-brain coronal sections. The mean relative volume of the anterior insular cortex was smaller than in non-addicted controls (3010 ± 614 *10-6 versus 3970 ± 1306 *10-6; p = 0.021). However, no significant differences in neuronal cell counts were observed. Therefore, the observed volume reduction appears to be a consequence of damaged connecting structures such as neuropil and glial cells. The findings were not confounded by age or duration of autolysis. Our results provide further evidence of structural deficits in key hubs of the addiction circuitry in heroin-dependent individuals and warrant further research in this area.

The many facets of CD26/dipeptidyl peptidase 4 and its inhibitors in disorders of the CNS - a critical overview.

Dipeptidyl peptidase 4 is a serine protease that cleaves X-proline or X-alanine in the penultimate position. Natural substrates of the enzyme are glucagon-like peptide-1, glucagon inhibiting peptide, glucagon, neuropeptide Y, secretin, substance P, pituitary adenylate cyclase-activating polypeptide, endorphins, endomorphins, brain natriuretic peptide, beta-melanocyte stimulating hormone and amyloid peptides as well as some cytokines and chemokines. The enzyme is involved in the maintenance of blood glucose homeostasis and regulation of the immune system. It is expressed in many organs including the brain. DPP4 activity may be effectively depressed by DPP4 inhibitors. Apart from enzyme activity, DPP4 acts as a cell surface (co)receptor, associates with adeosine deaminase, interacts with extracellular matrix, and controls cell migration and differentiation. This review aims at revealing the impact of DPP4 and DPP4 inhibitors for several brain diseases (virus infections affecting the brain, tumours of the CNS, neurological and psychiatric disorders). Special emphasis is given to a possible involvement of DPP4 expressed in the brain.While prominent contributions of extracerebral DPP4 are evident for a majority of diseases discussed herein; a possible role of "brain" DPP4 is restricted to brain cancers and Alzheimer disease. For a number of diseases (Covid-19 infection, type 2 diabetes, Alzheimer disease, vascular dementia, Parkinson disease, Huntington disease, multiple sclerosis, stroke, and epilepsy), use of DPP4 inhibitors has been shown to have a disease-mitigating effect. However, these beneficial effects should mostly be attributed to the depression of "peripheral" DPP4, since currently used DPP4 inhibitors are not able to pass through the intact blood-brain barrier.

Changes in leukocytes and CRP in different stages of major depression.

BACKGROUND: We recently reported increased levels of neutrophils, monocytes and C-reactive protein (CRP) correlated with symptom severity in acute schizophrenia. Here, we investigated if a similar pattern of innate immune system activation occurs in major depression (MD). METHODS: We assessed differential blood counts, CRP, depression symptoms (HAMD-21) and psychosocial functioning (GAF) in controls (n = 129) and patients with first (FEMD: n = 82) or recurrent (RMD: n = 47) disease episodes of MD at baseline (T0; hospital admission) and after 6-weeks treatment (T6). RESULTS: Considering smoking, BMI and gender as covariates, neutrophils (FEMD: p = 0.034, RMD: p = 0.034) and CRP (FEMD: p < 0.001, RMD: p = 0.021) were higher, and eosinophils (FEMD: p = 0.005, RMD: p = 0.004) lower in patients versus controls at T0. Baseline lymphocyte counts were elevated in RMD (p = 0.003) but not FEMD. Results were confirmed by analyses of nonsmokers. At follow-up, eosinophils rose significantly in FEMD (p = 0.011) but no significant changes were observed in RMD. Improvement in HAMD-21 correlated with T0-T6 changes of neutrophil counts in FEMD (r = 0.364, p = 0.024). Compared with our previous schizophrenia study, raised baseline neutrophil and reduced eosinophil counts in MD had smaller effect sizes and treatment had a weaker association with T0-T6 changes in neutrophils. In addition, lymphocytes were elevated at T0 in recurrent MD but not in schizophrenia patients. CONCLUSIONS: These findings suggest that innate immunity may be involved in early stages of MD, and adaptive immunity may be involved in chronic disease. Thus, further studies may lead to new disease stage-dependent MD treatment strategies targeting different aspects of immune system activation.

Testing for Thyroid Peroxidase and Antineuronal Antibodies in Depression and Schizophrenia.

Dietary interventions and physical exercise may improve some symptoms in mental illnesses such as major depression and schizophrenia. Hashimoto's thyroiditis is a known risk factor for these conditions and is marked by the presence of circulating antibodies to thyroid peroxidase (TPO) and thyroglobulin (TG). This chapter presents a protocol to determine if patients with major depression or schizophrenia contain high circulating levels of these antibodies relative to healthy controls. We also describe a procedure testing for the presence of other circulating biomarkers related to brain function, including antibodies directly related to neuronal function. This analysis was performed by screening biochip mosaics of frozen tissue sections and transfected HEK293 cells expressing target antigens using patient and control sera. Finally, we describe a correlation analysis of these markers with symptom scores at baseline and after 6 weeks treatment of the patients using antipsychotics or antidepressants as appropriate.

Reduced GABAergic neuropil and interneuron profiles in schizophrenia: Complementary analysis of disease course-related differences.

BACKGROUND: GABAergic interneuron dysfunction has been implicated in the pathophysiology of schizophrenia. Expression of glutamic acid decarboxylase (GAD), a key enzyme in GABA synthesis, may also be altered. Here, we have simultaneously evaluated GAD-immunoreactive (GAD-ir) neuropil and cell profiles in schizophrenia-relevant brain regions, and analysed disease-course related differences. METHODS: GAD65/67 immunoreactivity was quantified in specific brain regions for profiles of fibres and cell bodies of interneurons by automated digital image analysis in post-mortem brains of 16 schizophrenia patients from paranoid (n = 10) and residual (n = 6) diagnostic subgroups and 16 matched controls. Regions of interest were superior temporal gyrus (STG) layers III and V, mediodorsal (MD) and laterodorsal (LD) thalamus, and hippocampal CA1 and dentate gyrus (DG) regions. RESULTS: A reduction in GAD-ir neuropil profiles (p < 0.001), particularly in STG layer V (p = 0.012) and MD (p = 0.001), paralleled decreased GAD-ir cell profiles (p = 0.029) in schizophrenia patients compared to controls. Paranoid schizophrenia patients had lower GAD-ir neuron cell profiles in STG layers III (p = 0.007) and V (p = 0.001), MD (p = 0.002), CA1 (p = 0.001) and DG (p = 0.043) than residual patients. There was no difference in GAD-ir neuropil profiles between paranoid and residual subgroups (p = 0.369). CONCLUSIONS: These results support the hypothesis of GABAergic dysfunction in schizophrenia. They show a more prominent reduction of GAD-ir interneurons in paranoid versus residual patients, suggestive of more pronounced GABAergic dysfunction in the former. Fully automated analyses of histological sections represent a step towards user-independent assessment of brain structure.

Molecular mimicry of NMDA receptors may contribute to neuropsychiatric symptoms in severe COVID-19 cases.

Approximately 30% of individuals with severe SARS-CoV-2 infections also develop neurological and psychiatric complaints. In rare cases, the occurrence of autoimmune encephalitis has been reported after SARS-CoV-2 infection. In this systematic review, we have identified eight SARS-CoV-2-associated cases of anti-NMDA receptor encephalitis. All had cerebrospinal fluid antibodies against the NMDA receptor and a recent onset of working memory deficits, altered mental status, or psychiatric symptoms, such as confusion, agitation, auditory hallucination, catatonia and speech dysfunction. All patients received high-dose steroid and immunoglobulin therapeutics and conditions improved in each case. These findings suggest that clinical attention should be paid to warning signs of autoimmune encephalitis in severe COVID-19 cases. If characteristic features of autoimmune encephalitis are present, autoantibody diagnostics should be performed and confirmed cases should be treated with immunotherapy to minimize neurological impairments.

The implications of hypothalamic abnormalities for schizophrenia.

Until a few years ago, the hypothalamus was believed to play only a marginal role in schizophrenia pathophysiology. However, recent findings show that this rather small brain region involved in many pathways found disrupted-in schizophrenia. Gross anatomic abnormalities (volume changes of the third ventricle, the hypothalamus, and its individual nuclei) as well as alterations at the cellular level (circumscribed loss of neurons) can be observed. Further, increased or decreased expression of hypothalamic peptides such as oxytocin, vasopressin, several factors involved in the regulation of appetite and satiety, endogenous opiates, products of schizophrenia susceptibility genes as well as of enzymes involved in neurotransmitter and neuropeptide metabolism have been reported in schizophrenia and/or animal models of the disease. Remarkably, although profound disturbances of the hypothalamus-pituitary-adrenal axis, hypothalamus-pituitary-thyroid axis, and the hypothalamus-pituitary-gonadal axis are typical signs of schizophrenia, there is currently no evidence for alterations in the expression of hypothalamic-releasing and inhibiting factors that control these hormonal axes. Finally, the implications of hypothalamus for disease-related disturbances of the sleep-wakefulness cycle and neuroimmune dysfunctions in schizophrenia are outlined.

Plasma Anthranilic Acid and Leptin Levels Predict HAM-D Scores in Depressed Women.

OBJECTIVES: Major depressive disorder (MDD) is associated with dysregulations of leptin and tryptophan-kynurenine (Trp-Kyn) (TKP) pathways. Leptin, a pro-inflammatory cytokine, activates Trp conversion into Kyn. However, leptin association with down-stream Kyn metabolites in MDD is unknown. METHODS: Fasting plasma samples from 29 acutely ill drug-naïve (n = 16) or currently non-medicated (⩾6 weeks; n = 13) MDD patients were analyzed for leptin, Trp, Kyn, its down-stream metabolites (anthranilic [AA], kynurenic [KYNA], xanthurenic [XA] acids and 3-hydroxykynurenine [3HK]), C-reactive protein (CRP), neopterin, body mass index (BMI), and insulin resistance (HOMA-IR). Depression severity was assessed by HAM-D-21. RESULTS: In female (n = 14) (but not in male) patients HAM-D-21 scores correlated with plasma levels of AA (but not other Kyn metabolites) (rho = -0.644, P = .009) and leptin (Spearman's rho = -0.775, P = .001). Inclusion of AA into regression analysis improved leptin prediction of HAM-D from 48.5% to 65.9%. Actual HAM-D scores highly correlated with that calculated by formula: HAM-D = 34.8518-(0.5660 × leptin [ng/ml] + 0.4159 × AA [nmol/l]) (Rho = 0.84, P = .00015). In male (n = 15) (but not in female) patients leptin correlated with BMI, waist circumference/hip ratio, CRP, and HOMA-IR. CONCLUSIONS: Present findings of gender specific AA/Leptin correlations with HAM-D are important considering that AA and leptin are transported from plasma into brain, and that AA formation is catalyzed by kynureninase-the only TKP gene associated with depression according to genome-wide analysis. High correlation between predicted and actual HAM-D warrants further evaluation of plasma AA and leptin as an objective laboratory test for the assessment of depression severity in female MDD patients.

Polyamines and polyamine-metabolizing enzymes in schizophrenia: Current knowledge and concepts of therapy.

Polyamines play preeminent roles in a variety of cellular functions in the central nervous system and other organs. A large body of evidence suggests that the polyamine pathway is prominently involved in the etiology and pathology of schizophrenia. Alterations in the expression and activity of polyamine metabolizing enzymes, as well as changes in the levels of the individual polyamines, their precursors and derivatives, have been measured in schizophrenia and animal models of the disease. Additionally, neuroleptic treatment has been shown to influence polyamine concentrations in brain and blood of individuals with schizophrenia. Thus, the polyamine system may appear to be a promising target for neuropharmacological treatment of schizophrenia. However, for a number of practical reasons there is currently only limited hope for a polyamine-based schizophrenia therapy.

Reduced habenular volumes and neuron numbers in male heroin addicts: a post-mortem study.

The Habenula is increasingly being investigated in addiction. Reduced volumes of other relevant brain regions in addiction, such as nucleus accumbens, globus pallidus and hypothalamus have been reported. Reduced volumes of the habenula as well as reduced neuronal cell count in the habenula have also been reported in mood disorders and an overlap between mood disorders and addiction is clinically widely recognized. Thus, our aim was to investigate possible volume and neuronal cell count differences in heroin addicts compared to healthy controls. Volumes of the medial (MHB) and lateral habenula (LHB) in heroin addicts (n = 12) and healthy controls (n = 12) were assessed by morphometry of 20 µm serial whole brain sections. Total brain volume was larger in the heroin group (mean 1466.6 ± 58.5 cm3 vs. mean 1331.5 ± 98.8 cm3), possibly because the heroin group was about 15 years younger (p = 0.001). Despite larger mean whole brain volume, the mean relative volume of the MHB was smaller than in healthy non-addicted controls (6.94 ± 2.38 × 10-6 vs.10.64 ± 3.22 × 10-6; p = 0.004). A similar finding was observed regarding relative volumes of the LHB (46.62 ± 10.90 × 10-6 vs. 63.05 ± 16.42 × 10-6 p = 0.009). In parallel, neuronal cell numbers were reduced in the MHB of heroin-addicted subjects (395,966 ± 184,178 vs. 644,149 ± 131,140; p < 0.001). These findings were not significantly confounded by age and duration of autolysis. Our results provide further evidence for brain-structural deficits in heroin addiction.

Association of thyroid peroxidase antibodies with anti-neuronal surface antibodies in health, depression and schizophrenia - Complementary linkage with somatic symptoms of major depression.

Hashimoto's thyroiditis has been associated with major depression (MD) and schizophrenia (Sz) in epidemiological studies. However, diagnostically relevant antibodies (Abs) against thyroid peroxidase (TPO) and thyroglobulin (Tg) do not act directly on neurons. We hypothesized that an increased prevalence of anti-brain-Abs in thyroid-Ab-carriers could be linked with MD and Sz even without clinically manifest Hashimoto's thyroiditis. Serum samples from 638 acutely-ill patients with MD, Sz or matched controls were systematically screened for TPO- and Tg-Abs, other endocrine-Abs and a spectrum of specific anti-brain-Abs (directed against neuronal cell surface, synaptic, other neuronal or glial proteins). Analyses were based on indirect immunofluorescence in biochip mosaics of frozen tissue sections and transfected HEK293 cells expressing respective recombinant target antigens. Psychopathology was assessed on admission and after 6 weeks treatment by HAMD-21 (in MD) or PANSS (in Sz). Seroprevalence of TPO- and/or Tg-Abs was comparable in ill and healthy individuals (MD ~10%, Sz ~7%, controls ~9%) but thyroid-Abs were associated with neuronal cell surface/synaptic-Abs (p = 0.005), particularly in schizophrenia. Thyroid Ab-positive MD patients showed higher HAMD-21 scores (particularly somatic symptoms) at baseline (p = 0.026) and better reduction of symptoms after 6 weeks (p = 0.049) than thyroid-Ab-negative patients. This was unrelated to antidepressant drug dosage, thyroid hormonal-, inflammation- and anti-brain-Ab-status. No link with PANSS scores was observed in Sz. In conclusion, the co-occurrence of thyroid-Abs and neuronal surface/synaptic-Abs may be associated with Sz. Future cerebrospinal fluid research may be promising to clarify if thyroid-Ab-associated neuronal-Abs reach the brain in Sz patients. Thyroid-Ab-related differences regarding disease-severity and -course in MD are currently unexplained, but may be caused by un-identified anti-brain-Abs or a direct action of TPO-Abs on astrocytes.

From putative brain tumor marker to high cognitive abilities: Emerging roles of a disintegrin and metalloprotease (ADAM) 12 in the brain.

ADAM (a disintergin and metalloprotease) 12 is a member of the large family of multidomain metalloprotease-disintegrins, which possess cell-binding and metalloprotease properties. The enzyme is responsible for the shedding of a number of membrane-bound proteins (heparin-binding-EGF, insulin-like growth factor 2-binding proteins 3 and 5, oxytocinase, glycoprotein non-metastatic melanoma protein B and basigin). In rat and human CNS, ADAM12 is predominantly localized in white and gray matter oligodendrocytes. In addition it can be detected in astrocytes, neurons and endothelial cells. Its function in healthy brain is not well established yet, but prominent roles in CNS development, myelination and high cognitive abilities are discussed. There is increasing evidence that ADAM12 is involved in numerous major diseases of the CNS, which are summarized in the present review (brain tumors, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer´s disease, stroke, schizophrenia, autism and bipolar disorder).

Measurement of a Surrogate Biomarker for Arginine Vasopressin Secretion in Association with Physiometric and Molecular Biomarkers of Aging.

A number of physiological changes are known to occur with aging, including increased fat mass, increased insulin resistance, and changes in the levels of circulating biomarkers such as lipids, growth factors, and hormones. Here, we present protocols for physiometric assessments, as well as measurements of circulating biomarkers of hormonal and growth factor function in individuals over the age range of 18-52 years. We also test for potential gender differences in the outcome measures.

Enhanced mitochondrial autophagy (mitophagy) in oligodendrocytes might play a role in white matter pathology in schizophrenia.

Disrupted white matter integrity is a typical feature of brain pathologic alterations in schizophrenia, which includes impaired myelination, decreased oligodendrocyte densities, distortion of their spatial distribution and deviations from normal oligodendrocyte cell morphology. While most genes expressed "in the remaining" oligodendrocytes are downregulated in schizophrenia, only a few are upregulated. To the latter group belong prohibitin 2 and DISC 1, which were recently identified as mitochondria-located mitophagy receptors. Their overexpression, together with greatly reduced numbers and densities of oligodendroglial mitochondria and the structurally "normal appearance of the remaining mitochondria" in these cells as reported by Uranova's group (Uranova et al., 2001, 2004, 2018), point to enhanced mitophagy in oligodendrocytes in schizophrenia, which is possibly even cell protective by preventing apoptosis. Since massive loss of white matter oligodendrocytes is a characteristic feature of schizophrenia, we assume that increased mitophagy is a late event in the development and/or further progression of white matter pathologic changes. Moreover, altered oligodendroglial mitophagy might in part result from antipsychotic treatment. Further studies are clearly needed to substantiate our hypothesis on enhanced mitochondrial autophagy in schizophrenia, whereby the "drug-naïve state" and the possible influence of antipsychotic treatment could be elegantly simulated using animal models of the disease.

Binding varicella zoster virus: an underestimated facet of insulin-degrading enzyme´s implication for Alzheimer´s disease pathology?

We shortly discuss a possible contribution of insulin-degrading enzyme to Alzheimer´s disease pathology by binding varicella zoster virus glycoprotein E, which increases the infectivity and cell-cell spread of the virus.

Innate Immune Cells and C-Reactive Protein in Acute First-Episode Psychosis and Schizophrenia: Relationship to Psychopathology and Treatment.

Innate immunity has been linked to initiation of Alzheimer's disease and multiple sclerosis. Moreover, risk of first-episode psychosis (FEP) and schizophrenia (Sz) is increased after various infections in predisposed individuals. Thus, we hypothesized an analogous role of innate immunity with increased C-reactive protein (CRP) in non-affective psychosis. Differential blood count, CRP, neutrophil and monocyte-macrophage activation markers, cortisol and psychotic symptoms (Positive and Negative Syndrome Scale [PANSS]) were assessed in controls (n = 294) and acutely ill unmedicated FEP (n = 129) and Sz (n = 124) patients at baseline and after 6 weeks treatment. Neutrophils, monocytes, and CRP were increased in patients vs controls at baseline (P < .001), and neutrophil and monocyte counts correlated positively with activation markers. Eosinophils were lower at baseline in FEP (P < .001) and Sz (P = .021) vs controls. Differences in neutrophils (P = .023), eosinophils (P < .001), and CRP (P < .001) were also present when controlling for smoking and cortisol, and partially remitted after antipsychotic treatment. FEP patients with high neutrophils (P = .048) or monocytes (P = .021) had higher PANSS-P scores at baseline but similar disease course. CRP correlated with PANSS-P at baseline (ρ = 0.204, P = .012). Improvement of positive symptoms after treatment correlated with declining neutrophils (ρ = 0.186, P = .015) or CRP (ρ = 0.237, P = .002) and rising eosinophils (ρ = -0.161, P = .036). In FEP, normalization of neutrophils (ρ = -0.231, P = .029) and eosinophils (ρ = 0.209, P = .048) correlated with drug dosage. In conclusion, innate immune system activation correlated with PANSS-P, supporting the immune hypothesis of psychosis. Neutrophil and monocyte counts and CRP levels may be useful markers of disease acuity, severity, and treatment response.

Insulin-signaling abnormalities in drug-naïve first-episode schizophrenia: Transduction protein analyses in extracellular vesicles of putative neuronal origin.

BACKGROUND: Metabolic syndrome and impaired insulin sensitivity may occur as side effects of atypical antipsychotic drugs. However, studies of peripheral insulin resistance using the homeostatic model assessment of insulin resistance (HOMA-IR) or oral glucose tolerance tests (OGTT) suggest that abnormal glucose metabolism is already present in drug-naive first-episode schizophrenia (DNFES). We hypothesized impairments of neuronal insulin signaling in DNFES. METHODS: To gain insight into neuronal insulin-signaling in vivo, we analyzed peripheral blood extracellular vesicles enriched for neuronal origin (nEVs). Phosphorylated insulin signal transduction serine-threonine kinases pS312-IRS-1, pY-IRS-1, pS473-AKT, pS9-GSK3ß, pS2448-mTOR, pT389-p70S6K and respective total protein levels were determined in plasma nEVs from 48 DNFES patients and healthy matched controls after overnight fasting. RESULTS: Upstream pS312-IRS-1 was reduced at trend level (p = 0.071; this condition may amplify IRS-1 signaling). Exploratory omnibus analysis of downstream serine-threonine kinases (AKT, GSK3ß, mTOR, p70S6K) revealed lower phosphorylated/total protein ratios in DNFES vs. controls (p = 0.013), confirming decreased pathway activation. Post-hoc-tests indicated in particular a reduced phosphorylation ratio of mTOR (p = 0.027). Phosphorylation ratios of p70S6K (p = 0.029), GSK3ß (p = 0.039), and at trend level AKT (p = 0.061), showed diagnosis-dependent statistical interactions with insulin blood levels. The phosphorylation ratio of AKT correlated inversely with PANSS-G and PANSS-total scores, and other ratios showed similar trends. CONCLUSION: These findings support the hypothesis of neuronal insulin resistance in DNFES, small sample sizes notwithstanding. The counterintuitive trend towards reduced pS312-IRS-1 in DNFES may result from adaptive feedback mechanisms. The observed changes in insulin signaling could be clinically meaningful as suggested by their association with higher PANSS scores.