Spike mutation resilient scFv76 antibody counteracts SARS-CoV-2 lung damage upon aerosol delivery.

The uneven worldwide vaccination coverage against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and emergence of variants escaping immunity call for broadly effective and easily deployable therapeutic agents. We have previously described the human single-chain scFv76 antibody, which recognizes SARS-CoV-2 Alpha, Beta, Gamma and Delta variants. We now show that scFv76 also neutralizes the infectivity and fusogenic activity of the Omicron BA.1 and BA.2 variants. Cryoelectron microscopy (cryo-EM) analysis reveals that scFv76 binds to a well-conserved SARS-CoV-2 spike epitope, providing the structural basis for its broad-spectrum activity. We demonstrate that nebulized scFv76 has therapeutic efficacy in a severe hACE2 transgenic mouse model of coronavirus disease 2019 (COVID-19) pneumonia, as shown by body weight and pulmonary viral load data. Counteraction of infection correlates with inhibition of lung inflammation, as observed by histopathology and expression of inflammatory cytokines and chemokines. Biomarkers of pulmonary endothelial damage were also significantly reduced in scFv76-treated mice. The results support use of nebulized scFv76 for COVID-19 induced by any SARS-CoV-2 variants that have emerged so far.

Drug-Free Nasal Spray as a Barrier against SARS-CoV-2 and Its Delta Variant: In Vitro Study of Safety and Efficacy in Human Nasal Airway Epithelia.

The nasal epithelium is a key portal for infection by respiratory viruses such as SARS-CoV-2 and represents an important target for prophylactic and therapeutic interventions. In the present study, we test the safety and efficacy of a newly developed nasal spray (AM-301, marketed as Bentrio) against infection by SARS-CoV-2 and its Delta variant on an in vitro 3D-model of the primary human nasal airway epithelium. Safety was assessed in assays for tight junction integrity, cytotoxicity and cilia beating frequency. Efficacy against SARS-CoV-2 infection was evaluated in pre-viral load and post-viral load application on airway epithelium. No toxic effects of AM-301 on the nasal epithelium were found. Prophylactic treatment with AM-301 significantly reduced viral titer vs. controls over 4 days, reaching a maximum reduction of 99% in case of infection from the wild-type SARS-CoV-2 variant and more than 83% in case of the Delta variant. When AM-301 administration was started 24 h after infection, viral titer was reduced by about 12-folds and 3-folds on Day 4. The results suggest that AM-301 is safe and significantly decelerates SARS-CoV-2 replication in cell culture inhibition assays of prophylaxis (pre-viral load application) and mitigation (post-viral load application). Its physical (non-pharmaceutical) mechanism of action, safety and efficacy warrant additional investigations both in vitro and in vivo for safety and efficacy against a broad spectrum of airborne viruses and allergens.

Human inhalable antibody fragments neutralizing SARS-CoV-2 variants for COVID-19 therapy.

As of December 2021, coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global emergency, and novel therapeutics are urgently needed. Here we describe human single-chain variable fragment (scFv) antibodies (76clAbs) that block an epitope of the SARS-CoV-2 spike protein essential for ACE2-mediated entry into cells. 76clAbs neutralize the Delta variant and other variants being monitored (VBMs) and inhibit spike-mediated pulmonary cell-cell fusion, a critical feature of COVID-19 pathology. In two independent animal models, intranasal administration counteracted the infection. Because of their high efficiency, remarkable stability, resilience to nebulization, and low cost of production, 76clAbs may become a relevant tool for rapid, self-administrable early intervention in SARS-CoV-2-infected subjects independently of their immune status.

Local circuit allowing hypothalamic control of hippocampal area CA2 activity and consequences for CA1.

The hippocampus is critical for memory formation. The hypothalamic supramammillary nucleus (SuM) sends long-range projections to hippocampal area CA2. While the SuM-CA2 connection is critical for social memory, how this input acts on the local circuit is unknown. Using transgenic mice, we found that SuM axon stimulation elicited mixed excitatory and inhibitory responses in area CA2 pyramidal neurons (PNs). Parvalbumin-expressing basket cells were largely responsible for the feedforward inhibitory drive of SuM over area CA2. Inhibition recruited by the SuM input onto CA2 PNs increased the precision of action potential firing both in conditions of low and high cholinergic tone. Furthermore, SuM stimulation in area CA2 modulated CA1 activity, indicating that synchronized CA2 output drives a pulsed inhibition in area CA1. Hence, the network revealed here lays basis for understanding how SuM activity directly acts on the local hippocampal circuit to allow social memory encoding.

Deletion of the Spata3 Gene Induces Sperm Alterations and In Vitro Hypofertility in Mice.

Thanks to the analysis of an Interspecific Recombinant Congenic Strain (IRCS), we previously defined the Mafq1 quantitative trait locus as an interval on mouse Chromosome 1 associated with male hypofertility and ultrastructural abnormalities. We identified the Spermatogenesis associated protein 3 gene (Spata3 or Tsarg1) as a pertinent candidate within the Mafq1 locus and performed the CRISPR-Cas9 mediated complete deletion of the gene to investigate its function. Male mice deleted for Spata3 were normally fertile in vivo but exhibited a drastic reduction of efficiency in in vitro fertilization assays. Mobility parameters were normal but ultrastructural analyses revealed acrosome defects and an overabundance of lipids droplets in cytoplasmic remnants. The deletion of the Spata3 gene reproduces therefore partially the phenotype of the hypofertile IRCS strain.

YIF1B mutations cause a post-natal neurodevelopmental syndrome associated with Golgi and primary cilium alterations.

Human post-natal neurodevelopmental delay is often associated with cerebral alterations that can lead, by themselves or associated with peripheral deficits, to premature death. Here, we report the clinical features of 10 patients from six independent families with mutations in the autosomal YIF1B gene encoding a ubiquitous protein involved in anterograde traffic from the endoplasmic reticulum to the cell membrane, and in Golgi apparatus morphology. The patients displayed global developmental delay, motor delay, visual deficits with brain MRI evidence of ventricle enlargement, myelination alterations and cerebellar atrophy. A similar profile was observed in the Yif1b knockout (KO) mouse model developed to identify the cellular alterations involved in the clinical defects. In the CNS, mice lacking Yif1b displayed neuronal reduction, altered myelination of the motor cortex, cerebellar atrophy, enlargement of the ventricles, and subcellular alterations of endoplasmic reticulum and Golgi apparatus compartments. Remarkably, although YIF1B was not detected in primary cilia, biallelic YIF1B mutations caused primary cilia abnormalities in skin fibroblasts from both patients and Yif1b-KO mice, and in ciliary architectural components in the Yif1b-KO brain. Consequently, our findings identify YIF1B as an essential gene in early post-natal development in human, and provide a new genetic target that should be tested in patients developing a neurodevelopmental delay during the first year of life. Thus, our work is the first description of a functional deficit linking Golgipathies and ciliopathies, diseases so far associated exclusively to mutations in genes coding for proteins expressed within the primary cilium or related ultrastructures. We therefore propose that these pathologies should be considered as belonging to a larger class of neurodevelopmental diseases depending on proteins involved in the trafficking of proteins towards specific cell membrane compartments.

Centrifugal projections to the main olfactory bulb revealed by transsynaptic retrograde tracing in mice.

A wide range of evidence indicates that olfactory perception is strongly involved in food intake. However, the polysynaptic circuitry linking the brain areas involved in feeding behavior to the olfactory regions is not well known. The aim of this article was to examine such circuits. Thus, we described, using hodological tools such as transsynaptic viruses (PRV152) transported in a retrograde manner, the long-distance indirect projections (two to three synapses) onto the main olfactory bulb (MOB). The ß-subunit of the cholera toxin which is a monosynaptic retrograde tracer was used as a control to be able to differentiate between direct and indirect projections. Our tracing experiments showed that the arcuate nucleus of the hypothalamus, as a major site for regulation of food intake, sends only very indirect projections onto the MOB. Indirect projections to MOB also originate from the solitary nucleus which is involved in energy homeostasis. Other indirect projections have been evidenced in areas of the reward circuit such as VTA and accumbens nucleus. In contrast, direct projections to the MOB arise from melanin-concentrating hormone and orexin neurons in the lateral hypothalamus. Functional significances of these projections are discussed in relation to the role of food odors in feeding and reward-related behavior.

Somatostatin Serves a Modulatory Role in the Mouse Olfactory Bulb: Neuroanatomical and Behavioral Evidence.

Somatostatin (SOM) and somatostatin receptors (SSTR1-4) are present in all olfactory structures, including the olfactory bulb (OB), where SOM modulates physiological gamma rhythms and olfactory discrimination responses. In this work, histological, viral tracing and transgenic approaches were used to characterize SOM cellular targets in the murine OB. We demonstrate that SOM targets all levels of mitral dendritic processes in the OB with somatostatin receptor 2 (SSTR2) detected in the dendrites of previously uncharacterized mitral-like cells. We show that inhibitory interneurons of the glomerular layer (GL) express SSTR4 while SSTR3 is confined to the granule cell layer (GCL). Furthermore, SOM cells in the OB receive synaptic inputs from olfactory cortical afferents. Behavioral studies demonstrate that genetic deletion of SSTR4, SSTR2 or SOM differentially affects olfactory performance. SOM or SSTR4 deletion have no major effect on olfactory behavioral performances while SSTR2 deletion impacts olfactory detection and discrimination behaviors. Altogether, these results describe novel anatomical and behavioral contributions of SOM, SSTR2 and SSTR4 receptors in olfactory processing.

sst2-receptor gene deletion exacerbates chronic stress-induced deficits: Consequences for emotional and cognitive ageing.

This study investigated whether sst2 gene deletion interacts with age and chronic stress exposure to produce exacerbated emotional and cognitive ageing. Middle-aged (10-12 month) sst2 knockout (sst2KO) and wild-type (WT) mice underwent an unpredictable chronic mild stress (UCMS) procedure for 6 weeks or no stress for control groups. This was followed by a battery of tests to assess emotional and cognitive functions and neuroendocrine status (CORT level). A re-evaluation was performed 6 months later (i.e. with 18-month-old mice). UCMS reproduced neuroendocrine and behavioral features of stress-related disorders such as elevated circulating CORT levels, physical deteriorations, increased anxiety- and depressive-like behaviors and working memory impairments. sst2KO mice displayed behavioral alterations which were similar to stressed WT and exhibited exacerbated changes following UCMS exposure. The evaluations performed in the older mice showed significant long-term effects of UCMS exposure. Old sst2KO mice previously exposed to UCMS exhibited spatial learning and memory accuracy impairments and high levels of anxiety-like behaviors which drastically added to the effects of normal ageing. Spatial abilities and emotionality scores (mean z-scores) measured both at the UCMS outcome and 6 months later were correlated with the initially measured CORT levels in middle-age. The present findings indicate that the deletion of the sst2 receptor gene produces chronic hypercorticosteronemia and exacerbates sensitivity to stressors which over time, have consequences on ageing brain function processes.

Relationships Between Lower Olfaction and Brain White Matter Lesions in Elderly Subjects with Mild Cognitive Impairment.

BACKGROUND: Olfactory impairment is reported in mild cognitive impairment (MCI) and Alzheimer's disease (AD) and is associated with hippocampal atrophy. In elderly people, dementia with AD neuropathology and white matter lesions (WML) is common. In this context, olfactory impairment could also depend on the presence of WML. OBJECTIVE: To assess the cross-sectional relationship between olfaction and WML in elderly subjects with MCI. METHODS: Consecutive subjects, >65 years old, diagnosed as MCI after a comprehensive neuropsychological assessment in an expert memory center, with a brain MRI performed within a year and without major depressive state, were included. Olfaction was assessed by the Brief Smell Identification Test (BSIT). Two trained neuroradiologists, blind to cognitive and olfaction status, visually assessed hippocampal atrophy according to Scheltens' scale and WML according to Fazekas criteria. RESULTS: Seventy-five MCI subjects (mean age (SD) = 77.1 (6.2) years, 74.7% of women) were included. After adjustment for age and sex, factors associated with low BSIT scores were older age (p = 0.007), lower BMI (p = 0.08), lower MMSE score (p = 0.05), lower FCRST (p = 0.008), hippocampal atrophy (p = 0.04), periventricular WML (p = 0.007), and deep WML burden (p = 0.005). In multivariate analysis, severe deep WML (OR (95% CI) = 6.29 (1.4-35.13), p = 0.02) remained associated with low BSIT score independently from hippocampal atrophy. CONCLUSION: In elderly MCI subjects, low olfactory performances are associated with WML, whose progression may be slowed by vascular treatments. A longitudinal study to evaluate whether the progression of WML, hippocampal atrophy and low olfactory function, can predict accurately conversion from MCI to dementia is ongoing.

Interneuron-specific signaling evokes distinctive somatostatin-mediated responses in adult cortical astrocytes.

The signaling diversity of GABAergic interneurons to post-synaptic neurons is crucial to generate the functional heterogeneity that characterizes brain circuits. Whether this diversity applies to other brain cells, such as the glial cells astrocytes, remains unexplored. Using optogenetics and two-photon functional imaging in the adult mouse neocortex, we here reveal that parvalbumin- and somatostatin-expressing interneurons, two key interneuron classes in the brain, differentially signal to astrocytes inducing weak and robust GABAB receptor-mediated Ca2+ elevations, respectively. Furthermore, the astrocyte response depresses upon parvalbumin interneuron repetitive stimulations and potentiates upon somatostatin interneuron repetitive stimulations, revealing a distinguished astrocyte plasticity. Remarkably, the potentiated response crucially depends on the neuropeptide somatostatin, released by somatostatin interneurons, which activates somatostatin receptors at astrocytic processes. Our study unveils, in the living brain, a hitherto unidentified signaling specificity between interneuron subtypes and astrocytes opening a new perspective into the role of astrocytes as non-neuronal components of inhibitory circuits.

Somatostatin-IRES-Cre Mice: Between Knockout and Wild-Type?

The neuropeptide somatostatin (SOM) is widely expressed in rodent brain and somatostatin-IRES-Cre (SOM-cre) mouse strains are increasingly used to unravel the physiology of SOM-containing neurons. However, while knock-in targeting strategy greatly improves Cre-Lox system accuracy, recent reports have shown that genomic insertion of Cre construct per se can markedly affect physiological function. We show that Cre transgene insertion into the 3'UTR of the somatostatin gene leads to the selective and massive depletion of endogenous SOM in all tested brain regions. It also strongly impacts SOM-related neuroendocrine responses in a similar manner to what has been reported for SST KO mice: increased corticosterone levels after 30-min restraint stress, decreased amplitude and regularity of ultradian growth hormone secretory patterns accompanied by changes in sexually dimorphic liver gene expression (serpina1, Cyp2b9, Cyp2a4, Cyp2d9, and Cyp7b1). In addition to demonstrating the need for examination of the consequences of Cre transgenesis, these results also reveal how this SOM-cre strain may be a useful tool in studying the functional consequences of moderate to low SOM levels as reported in neurological and psychiatric disorders.

Roles of Hippocampal Somatostatin Receptor Subtypes in Stress Response and Emotionality.

Altered brain somatostatin functions recently appeared as key elements for the pathogenesis of stress-related neuropsychiatric disorders. The hippocampus exerts an inhibitory feedback on stress but the mechanisms involved remain unclear. We investigated herein the role of hippocampal somatostatin receptor subtypes in both stress response and behavioral emotionality using C57BL/6, wild type and sst2 or sst4 knockout mice. Inhibitory effects of hippocampal infusions of somatostatin agonists on stress-induced hypothalamo-pituitary-adrenal axis (HPA) activity were tested by monitoring peripheral blood and local hippocampus corticosterone levels, the latter by using microdialysis. Anxiolytic and antidepressant-like effects were determined in the elevated-plus maze, open field, forced swimming, and stress-sensitive beam walking tests. Hippocampal injections of somatostatin analogs and sst2 or sst4, but not sst1 or sst3 receptor agonists produced rapid and sustained inhibition of HPA axis. sst2 agonists selectively produced anxiolytic-like behaviors whereas both sst2 and sst4 agonists had antidepressant-like effects. Consistent with these findings, high corticosterone levels and anxiety were found in sst2KO mice and depressive-like behaviors observed in both sst2KO and sst4KO strains. Both hippocampal sst2 and sst4 receptors selectively inhibit stress-induced HPA axis activation but mediate anxiolytic and antidepressive effects through distinct mechanisms. Such results are to be accounted for in development of pathway-specific somatostatin receptor agents in the treatment of hypercortisolism (Cushing's disease) and stress-related neuropsychiatric disorders.

Low Serum Insulin-Like Growth Factor-I Predicts Cognitive Decline in Alzheimer's Disease.

BACKGROUND: The relationship between the insulin-like growth factor-I (IGF-I) system and Alzheimer's disease (AD) is mostly based on transversal studies. It remains, however, to demonstrate whether IGF-I is associated with cognitive decline over time in AD. OBJECTIVE: The objective of the study was to analyze the course of cognitive decline of AD subjects over a 24-month period in relation to serum IGF-I and insulin-like growth factor binding protein-3 (IGFBP-3) measured at baseline. METHODS: Data are from the SIGAL follow-up study. IGF-I and IGFBP-3 were measured in AD subjects who performed a Mini-Mental State Examination (MMSE) every 6 months for 2 years. MMSE course was analyzed using a mixed model with random intercept and slope function. RESULTS: Among the 200 AD participants, 146 (mean age = 81.1 (standard deviation (SD) = 5.9) years, 62.6% of women) had at least one follow-up visit. Mean IGF-I at baseline was 147.8 (74.2) ng/mL. Hundred forty-six participants (62.6%) had at least one follow-up visit. Mean MMSE was 21.7 (4.7)/30 and dropped on average by 2.28 points per year. MMSE decline was steeper among participants with lower IGF-I. For each decrease of 1 SD of IGF-I, subjects lost an additional 0.63 points per year in MMSE, e.g., participants with IGF-I level of 74 ng/mL lost 2.91 MMSE points per year whereas participants with IGF-I of 222 ng/mL lost 1.65 MMSE points per year. There was no association between IGFBP-3 and cognitive decline. CONCLUSION: Lower baseline serum IGF-I was associated with faster cognitive decline in AD over a 2-year period.

Insulin-Like Growth Factor-I, Insulin-Like Growth factor Binding Protein-3 and Blood Hemoglobin Concentration in an Elderly Population.

BACKGROUND: Insulin-like growth factor-I (IGF-I) serum level decreases with age, and this decrease may underlie hemoglobin (Hb) decrease. The objective of the study was to assess the relationship between IGF-I and insulin-like growth factor binding protein-3 (IGFBP-3) serum levels and Hb, after adjustment especially for major nutritional factors in an elderly population because IGF-I system depends on nutritional state, often impaired in the elderly. METHODS: Hemoglobin concentration was tested for 672 participants evaluated during an outpatient geriatric assessment. IGF-I and IGFBP-3 serum levels were assessed by Enzyme Linked Immunosorbent Assay. The molar ratio of IGF-I/IGFBP-3 that reflects the bioavailable IGF-I was calculated. Levels of IGF-I and IGFBP-3 were plotted against quartiles of Hb. Final linear models for IGF-I, IGFBP-3 and ratio molar included factors that could modify the Hb level. RESULTS: Mean age (SD) of the sample was 78.0 (8.5) years old and 32% were men. After adjustment for age and sex, IGF-I serum level, IGFBP-3 serum level and molar ratio significantly increased with increasing quartiles of Hb. After adjustment for age, gender, diabetes, albumin, pre-albumin, renal function, total cholesterol, angiotensin converting enzyme inhibitors and angiotensin II receptor blockers consumption, C-Reactive Protein, Hb was significantly associated and with IGF-I level (p = .002) and molar ratio (p = .02). CONCLUSIONS: IGF-I serum level and IGF-I/IGFBP-3 molar ratio were associated with Hb in an elderly population, independently of nutritional biological parameters. Thus, the association between the IGF-I system and Hb merits further investigation to determine whether interventions that modulate circulating IGF-I or IGF-I/BP3 ratio might preserve Hb in the elderly.

Aging, but not tau pathology, impacts olfactory performances and somatostatin systems in THY-Tau22 mice.

Somatostatin (SOM) cortical levels decline in Alzheimer's disease (AD) in correlation with cognitive impairment severity, the latter being closely related to the presence of neurofibrillary tangles. Impaired olfaction is another hallmark of AD tightly related to tau pathology in the olfactory pathways. Recent studies showed that SOM modulates olfactory processing, suggesting that alterations in SOM levels participate to olfactory deficits in AD. Herein, we first observed that human olfactory peduncle and cortex are enriched in SOM cells and fibers, in aged postmortem brains. Then, the possible link between SOM alterations and olfactory deficits was evaluated by exploring the impact of age and tau hyperphosphorylation on olfactory SOM networks and behavioral performances in THY-Tau22 mice, a tauopathy transgenic model. Distinct molecular repertoires of SOM peptide and receptors were associated to sensory or cortical olfactory processing structures. Aging mainly affected SOM neurotransmission in piriform and entorhinal cortex in wild-type mice, although olfactory performances decreased. However, no further olfactory impairment was evidenced in THY-Tau22 mice until 12 months although tau pathology early affected olfactory cortical structures. Thus, tau hyperphosphorylation per se has a limited impact on olfactory performances in THY-Tau22 mice.

Relationships between Personality Traits, Medial Temporal Lobe Atrophy, and White Matter Lesion in Subjects Suffering from Mild Cognitive Impairment.

Mild cognitive impairment (MCI) is a heterogeneous cognitive status that can be a prodromal stage of Alzheimer's disease (AD). It is particularly relevant to focus on prodromal stages of AD such as MCI, because patho-physiological abnormalities of AD start years before the dementia stage. Medial temporal lobe (MTL) atrophy resulting from AD lesions and cerebrovascular lesions [i.e., white matter lesions (WML), lacunar strokes, and strokes] are often revealed concurrently on magnetic resonance imaging (MRI) in MCI subjects. Personality changes have been reported to be associated with MCI status and early AD. More specifically, an increase in neuroticism and a decrease in conscientiousness have been reported, suggesting that higher and lower scores, respectively, in neuroticism and conscientiousness are associated with an increased risk of developing the disease. However, personality changes have not been studied concomitantly with pathological structural brain alterations detected on MRI in patients suffering from MCI. Therefore, the objective of the present study was to assess the relationship between MTL atrophy, WML, lacunar strokes, and personality traits in such patients. The severity of WML was strongly associated with lower levels of conscientiousness and higher levels of neuroticism. Conversely, no association was detected between personality traits and the presence of lacunar strokes or MTL atrophy. Altogether, these results strongly suggest that personality changes occurring in a MCI population, at high risk of AD, are associated with WML, which can induce executive dysfunctions, rather than with MTL atrophy.

Insulin-like growth factor I, insulin-like growth factor binding protein 3, and atrial fibrillation in the elderly.

BACKGROUND: Insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein 3 (IGFBP-3) are involved in oxidative stress and atherosclerosis; however, the relationship between the IGF-I system and atrial fibrillation (AF) is not known. The objective of this analysis was to assess, the relationship between IGF-I and IGFBP-3 serum levels and AF among elderly participants. METHODS: In this cross-sectional study, 719 participants (mean age [SD] years: 78.2 [6.8]; 31.8% men) were evaluated during an outpatient geriatric assessment. AF was determined by electrocardiogram or medical record. Participants were classified into two groups: Participants with AF (n = 91) or without AF (n = 628). IGF-I and IGFBP-3 serum levels were determined by enzyme linked immunosorbent assay. RESULTS: After adjusting for age and sex, the mean IGF-I and IGFBP-3 serum levels were significantly lower among AF participants than among non-AF participants (mean IGF-I ng/mL [SD] = 133.8 [66.6] vs 157.9 [80.0], p = .02; mean IGFBP-3 ng/mL [SD] = 3,653 [1,393] vs 4,151 [1,583], p = .03, respectively). After adjusting for confounding factors (age, gender, beta blocker medication, heart rate, hypertension, stroke, and chronic heart failure), low IGF-I serum level (OR [95% CI] = 0.66 [0.49-0.87]) and low IGFBP-3 serum level (0.71 [0.54-0.93]) remained independent determinants of AF. CONCLUSIONS: Low IGF-I and low IGFBP-3 serum levels were independently associated with AF in this elderly population. This result should be confirmed in a longitudinal study to evaluate whether IGF-I and/or IGFBP-3 serum levels are predictive of incident AF.

Somatostatinergic systems: an update on brain functions in normal and pathological aging.

Somatostatin is highly expressed in mammalian brain and is involved in many brain functions such as motor activity, sleep, sensory, and cognitive processes. Five somatostatin receptors have been described: sst(1), sst(2) (A and B), sst(3), sst(4), and sst(5), all belonging to the G-protein-coupled receptor family. During the recent years, numerous studies contributed to clarify the role of somatostatin systems, especially long-range somatostatinergic interneurons, in several functions they have been previously involved in. New advances have also been made on the alterations of somatostatinergic systems in several brain diseases and on the potential therapeutic target they represent in these pathologies.

Insulin-like growth factor-I and insulin-like growth factor binding protein-3 in Alzheimer's disease.

CONTEXT: Few large studies have been conducted to assess the relationship between circulating IGF and late-life cognition. OBJECTIVE: The aim of the study was to assess the relationship between IGF-I and IGF binding protein-3 (IGFBP-3) serum levels and cognitive impairment, including Alzheimer's disease (AD). METHODS: In this multicentric cross-sectional study, 694 elderly subjects (218 men, 476 women; 78.6 ± 6.7 yr old) were included; 481 had memory complaints and were diagnosed, after comprehensive cognitive assessment, with AD (n = 224) or mild cognitive impairment (MCI) (n = 257). The control group was comprised of 213 subjects without memory complaint and with normal cognition (recruited among patients' caregivers). IGF-I and IGFBP-3 serum levels were determined by ELISA. RESULTS: IGF-I and IGFBP-3 serum levels were significantly associated with cognitive status in men (IGF-I, 137 ± 69 ng/ml for AD vs. 178 ± 88 ng/ml for MCI and 172 ± 91 ng/ml for controls, P = 0.01; IGFBP-3, 3675 ± 1542 ng/ml for AD vs. 4143 ± 1828 ng/ml for MCI and 4488 ± 1893 ng/ml for controls, P = 0.04). In women, IGFBP-3 was significantly associated with cognitive status (3781 ± 1351 ng/ml for AD vs. 4190 ± 1408 ng/ml for MCI and 4390 ± 1552 ng/ml for controls; P < 0.001), but no significant differences between groups for IGF-I occurred. After adjustment for confounding variables (age, educational level, body mass index, diabetes, apolipoprotein E ε4 status), logistic regression indicated that IGF-I [odds ratio (95% confidence interval) = 0.48 (0.26-0.88)] and IGFBP-3 [odds ratio (95% confidence interval) = 0.71 (0.52-0.97)] serum levels were independently associated with AD in men, but not in women. CONCLUSIONS: We report a significant association between low IGF-I and IGFBP-3 serum levels and AD in men, but not in women.