“…In the present studies, 5xFAD/MMP9KO mice had significantly lower locomotor activity compared to the 5xFAD mice as measured by distance travelled and average velocity, again suggesting MMP9 may be influencing anxiety-related behavior. In fact, MMP9 has been associated with an increased susceptibility to anxiety disorders [ 112 ] as well as showing elevated levels in other psychiatric illnesses [ 113 – 115 ]. Human genomic and proteomic studies have revealed that aberrant inflammatory responses, gene regulation, and synaptic plasticity are major players underlying neuropsychiatric disorders.…”
Background
Matrix metallopeptidase 9 (MMP9) has been implicated in a variety of neurological disorders, including Alzheimer’s disease (AD), where MMP9 levels are elevated in the brain and cerebrovasculature. Previously our group demonstrated apolipoprotein E4 (apoE4) was less efficient in regulating MMP9 activity in the brain than other apoE isoforms, and that MMP9 inhibition facilitated beta-amyloid (Aβ) elimination across the blood–brain barrier (BBB)
Methods
In the current studies, we evaluated the impact of MMP9 modulation on Aβ disposition and neurobehavior in AD using two approaches, (1) pharmacological inhibition of MMP9 with SB-3CT in apoE4 x AD (E4FAD) mice, and (2) gene deletion of MMP9 in AD mice (MMP9KO/5xFAD)
Results
Treatment with the MMP9 inhibitor SB-3CT in E4FAD mice led to reduced anxiety compared to placebo using the elevated plus maze. Deletion of the MMP9 gene in 5xFAD mice also reduced anxiety using the open field test, in addition to improving sociability and social recognition memory, particularly in male mice, as assessed through the three-chamber task, indicating certain behavioral alterations in AD may be mediated by MMP9. However, neither pharmacological inhibition of MMP9 or gene deletion of MMP9 affected spatial learning or memory in the AD animals, as determined through the radial arm water maze. Moreover, the effect of MMP9 modulation on AD neurobehavior was not due to changes in Aβ disposition, as both brain and plasma Aβ levels were unchanged in the SB-3CT-treated E4FAD animals and MMP9KO/AD mice compared to their respective controls.
Conclusions
In total, while MMP9 inhibition did improve specific neurobehavioral deficits associated with AD, such as anxiety and social recognition memory, modulation of MMP9 did not alter spatial learning and memory or Aβ tissue levels in AD animals. While targeting MMP9 may represent a therapeutic strategy to mitigate aspects of neurobehavioral decline in AD, further work is necessary to understand the nature of the relationship between MMP9 activity and neurological dysfunction.
“…In the present studies, 5xFAD/MMP9KO mice had significantly lower locomotor activity compared to the 5xFAD mice as measured by distance travelled and average velocity, again suggesting MMP9 may be influencing anxiety-related behavior. In fact, MMP9 has been associated with an increased susceptibility to anxiety disorders [ 112 ] as well as showing elevated levels in other psychiatric illnesses [ 113 – 115 ]. Human genomic and proteomic studies have revealed that aberrant inflammatory responses, gene regulation, and synaptic plasticity are major players underlying neuropsychiatric disorders.…”
Background
Matrix metallopeptidase 9 (MMP9) has been implicated in a variety of neurological disorders, including Alzheimer’s disease (AD), where MMP9 levels are elevated in the brain and cerebrovasculature. Previously our group demonstrated apolipoprotein E4 (apoE4) was less efficient in regulating MMP9 activity in the brain than other apoE isoforms, and that MMP9 inhibition facilitated beta-amyloid (Aβ) elimination across the blood–brain barrier (BBB)
Methods
In the current studies, we evaluated the impact of MMP9 modulation on Aβ disposition and neurobehavior in AD using two approaches, (1) pharmacological inhibition of MMP9 with SB-3CT in apoE4 x AD (E4FAD) mice, and (2) gene deletion of MMP9 in AD mice (MMP9KO/5xFAD)
Results
Treatment with the MMP9 inhibitor SB-3CT in E4FAD mice led to reduced anxiety compared to placebo using the elevated plus maze. Deletion of the MMP9 gene in 5xFAD mice also reduced anxiety using the open field test, in addition to improving sociability and social recognition memory, particularly in male mice, as assessed through the three-chamber task, indicating certain behavioral alterations in AD may be mediated by MMP9. However, neither pharmacological inhibition of MMP9 or gene deletion of MMP9 affected spatial learning or memory in the AD animals, as determined through the radial arm water maze. Moreover, the effect of MMP9 modulation on AD neurobehavior was not due to changes in Aβ disposition, as both brain and plasma Aβ levels were unchanged in the SB-3CT-treated E4FAD animals and MMP9KO/AD mice compared to their respective controls.
Conclusions
In total, while MMP9 inhibition did improve specific neurobehavioral deficits associated with AD, such as anxiety and social recognition memory, modulation of MMP9 did not alter spatial learning and memory or Aβ tissue levels in AD animals. While targeting MMP9 may represent a therapeutic strategy to mitigate aspects of neurobehavioral decline in AD, further work is necessary to understand the nature of the relationship between MMP9 activity and neurological dysfunction.
“…In addition, animal studies, in particular in non-human primates, enabling a translational approach, should further advance our understanding of the molecular and genetic underpinnings of anxiety-related brain changes (cf. [ 26 , 175 ]). Fig.…”
BackgroundSocial anxiety disorder (SAD) is a disabling psychiatric condition with a genetic background. Brain alterations in gray matter (GM) related to SAD have been previously reported, but it remains to be elucidated whether GM measures are candidate endophenotypes of SAD. Endophenotypes are measurable characteristics on the causal pathway from genotype to phenotype, providing insight in genetically-based disease mechanisms. Based on a review of existing evidence, we examined whether GM characteristics meet two endophenotype criteria, using data from a unique sample of SAD-patients and their family-members of two generations. First, we investigated whether GM characteristics co-segregate with social anxiety within families genetically enriched for SAD. Secondly, heritability of the GM characteristics was estimated.MethodsFamilies with a genetic predisposition for SAD participated in the Leiden Family Lab study on SAD; T1-weighted MRI brain scans were acquired (n = 110, 8 families). Subcortical volumes, cortical thickness and cortical surface area were determined for a-priori determined regions of interest (ROIs). Next, associations with social anxiety and heritabilities were estimated.FindingsSeveral subcortical and cortical GM characteristics, derived from frontal, parietal and temporal ROIs, co-segregated with social anxiety within families (uncorrected p-level) and showed moderate to high heritability.InterpretationThese findings provide preliminary evidence that GM characteristics of multiple ROIs, which are distributed over the brain, are candidate endophenotypes of SAD. Thereby, they shed light on the genetic vulnerability for SAD. Future research is needed to confirm these results and to link them to functional brain alterations and to genetic variations underlying these GM changes.FundLeiden University Research Profile ‘Health, Prevention and the Human Life Cycle’.
“…Anxiety disorders are among the most common psychiatric disorders and their prevalence ranges from 7.3% to 11.6% (Baxter, Scott, Vos, & Whiteford, 2013). Many studies have focused on their associations with genetic (McGregor et al, 2018), neurocognitive (Bishop, 2007), and environmental stress (Phillips, Hammen, Brennan, Najman, & Bor, 2005; Sharma, Powers, Bradley, & Ressler, 2016). Contrasting findings in recent years revealed that intimate relationships, namely family relationships, play a central role in the onset, course, and treatment of these kinds of disorders (Eley, Collier, & McGuffin, 2002; Foran, Whisman, & Beach, 2015).…”
Bowen’s multigenerational family theory emphasizes the importance of autonomy and interdependence in individual development and focuses on the role played by the differentiation of self processes on the psychological health at the individual, dyadic, and systemic levels. Starting from these premises, the main objective of our investigation was to explore the differences, in the levels of anxiety and differentiation of self, between a control group ( n = 69) and a sample of adults seeking therapeutic services for anxiety ( n = 47). To better specify our results, in a second step, we also explored which of the differentiation of self dimensions could increase or reduce the likelihood that an individual belonged to the anxiety group or to the control group. We found that lower levels of I-position, and higher levels of emotional cutoff and fusion with others, display higher levels of anxiety-related problems. Moreover, emotional cutoff and fusion with other traits emerged as a predictor of the probability of seeking support for anxiety disorders.
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