Amyloid-ß (Aß) immunotherapy induced microhemorrhages are associated with activated perivascular macrophages and peripheral monocyte recruitment in Alzheimer's disease mice.

BACKGROUND: Amyloid-related imaging abnormalities (ARIA) have been identified as the most common and serious adverse events resulting from pathological changes in the cerebral vasculature during several recent anti-amyloid-ß (Aß) immunotherapy trials. However, the precise cellular and molecular mechanisms underlying how amyloid immunotherapy enhances cerebral amyloid angiopathy (CAA)-mediated alterations in vascular permeability and microhemorrhages are not currently understood. Interestingly, brain perivascular macrophages have been implicated in regulating CAA deposition and cerebrovascular function however, further investigations are required to understand how perivascular macrophages play a role in enhancing CAA-related vascular permeability and microhemorrhages associated with amyloid immunotherapy. METHODS: In this study, we examined immune responses induced by amyloid-targeting antibodies and CAA-induced microhemorrhages using histology and gene expression analyses in Alzheimer's disease (AD) mouse models and primary culture systems. RESULTS: In the present study, we demonstrate that anti-Aß (3D6) immunotherapy leads to the formation of an antibody immune complex with vascular amyloid deposits and induces the activation of CD169+ perivascular macrophages. We show that macrophages activated by antibody mediated Fc receptor signaling have increased expression of inflammatory signaling and extracellular matrix remodeling genes such as Timp1 and MMP9 in vitro and confirm these key findings in vivo. Finally, we demonstrate enhanced vascular permeability of plasma proteins and recruitment of inflammatory monocytes around vascular amyloid deposits, which are associated with hemosiderin deposits from cerebral microhemorrhages, suggesting the multidimensional roles of activated perivascular macrophages in response to Aß immunotherapy. CONCLUSIONS: In summary, our study establishes a connection between Aß antibodies engaged at CAA deposits, the activation of perivascular macrophages, and the upregulation of genes involved in vascular permeability. However, the implications of this phenomenon on the susceptibility to microhemorrhages remain to be fully elucidated. Further investigations are warranted to determine the precise role of CD169 + perivascular macrophages in enhancing CAA-mediated vascular permeability, extravasation of plasma proteins, and infiltration of immune cells associated with microhemorrhages.

Decreased sensitivity of NMDA receptors on dopaminergic neurons from the posterior ventral tegmental area following chronic nondependent alcohol consumption.

BACKGROUND: The mesocorticolimbic dopamine system mediates the reinforcing effects of salient stimuli, including drugs of abuse. Nondependent chronic alcohol consumption modifies this system, resulting in an increased number of spontaneously active dopamine neurons in the posterior ventral tegmental area (VTA) of alcohol-preferring (P) rats. Enhanced responses of postsynaptic glutamate receptors may contribute to the increase in active dopamine neurons. Thus, excitations of putative dopamine neurons to locally applied N-methyl-d-aspartic acid (NMDA; glutamate receptor subtype agonist) were evaluated. METHODS: P rats were assigned to alcohol naïve (water only) or alcohol drinking (continuous access to 15% alcohol and water for 8 consecutive weeks) groups. Responses of 23 putative dopamine neurons from naïve rats and 19 putative dopamine neurons from drinking rats were assessed in vivo using microiontophoretically applied NMDA. Current-response curves for firing frequency and burst activity were constructed using nonlinear mixed effects models. Between-group comparisons were made for EC(50) (effective current producing a half maximal excitatory response), E(max) (maximal excitatory effect), and C(DB) (the current at which depolarization block-marked decrease in neuronal activity-occurred). RESULTS: Drinking P rats steadily consumed alcohol over the 8-week protocol and did not exhibit signs of dependence or withdrawal. Putative dopamine neurons from drinking rats exhibited resistance to depolarization block (higher C(DB) values) and required larger doses of NMDA to elicit moderate excitatory responses (higher EC(50) values), consistent with decreased receptor affinity. Maximal excitatory responses (E(max) ) did not differ between the groups, consistent with no change in receptor number. Blood alcohol was at undetectable levels at the time of experimentation. CONCLUSIONS: NMDA receptor sensitivity is decreased on posterior VTA putative dopamine neurons in P rats on a nondependent schedule of alcohol consumption. Mechanisms underlying increased spontaneous dopamine neuron activity may be independent of changes in NMDA receptor function. Decreased NMDA receptor sensitivity may precede the development of dependence.

Combined effect of depressive symptoms and hostility on autonomic nervous system function.

Depression and hostility have been separately related to indicators of sympathetic hyperactivation and parasympathetic hypoactivation. We examined the associations of depressive symptoms, hostility, and their interaction with pre-ejection period (PEP) and high frequency heart rate variability (HRV), specific indices of sympathetic and parasympathetic cardiac control, respectively. Healthy, young adults (N=120) completed questionnaires assessing depressive symptoms and hostility and underwent autonomic testing. Although main effects were not observed, a depressive symptoms×hostility interaction was detected for PEP (ß=.25, p=.01). Simple slope analyses revealed that hostility was negatively related to PEP among individuals with low depressive symptoms but was not associated with PEP among those with mild-to-moderate depressive symptoms. No interaction effect was detected for high frequency HRV. Our findings suggest that depressive symptoms may moderate the link between hostility and sympathetic activation such that hostility is accompanied by sympathetic hyperactivation only when depressive symptoms are minimal.

Hostility now, depression later? Longitudinal associations among emotional risk factors for coronary artery disease.

BACKGROUND/PURPOSE: Given that emotional risk factors for coronary artery disease (CAD) tend to cluster within individuals, surprisingly little is known about how these negative emotions might influence one another over time. We examined the longitudinal associations among measures of depressive symptoms and hostility/anger in a cohort of 296 healthy, older adults. METHODS: Participants completed the Beck Depression Inventory-II (BDI-II), Cook-Medley Hostility (Ho) scale, and Anger-In and Anger-Out subscales of the State-Trait Anger Expression Inventory at baseline and 6-year follow-up. We conducted a series of path analyses to evaluate the directionality of the depression-hostility/anger relationship. RESULTS: Baseline Ho scale was a predictor of 6-year increases in BDI-II (beta = 0.15, p = 0.004), Anger-In (beta = 0.14, p = 0.002), and Anger-Out (beta = 0.11, p = 0.01). In contrast, baseline BDI-II, Anger-In, and Anger-Out did not predict change in any of the emotional variables. Additional path analytic models revealed that the pattern of relationships was not altered after controlling for demographic, biomedical, and behavioral covariates; anxiety symptoms; social support; and subjective sleep quality. CONCLUSIONS: The present results suggest that the cognitive aspects of hostility/anger may precede and independently predict future increases in depressive symptoms but not vice versa. Our findings lead us to speculate that (a) hostility may exert part of its cardiotoxic influence by acting to precipitate and/or maintain symptoms of depression and that (b) the potency of depression interventions designed to improve cardiovascular outcomes might be enhanced by incorporating treatments addressing hostility.