[show abstract][hide abstract] ABSTRACT: Glutamatergic signaling through N-methyl-D-aspartate receptors (NMDARs) is required for synaptic plasticity. Disruptions in glutamatergic signaling are proposed to contribute to the behavioral and cognitive deficits observed in schizophrenia (SZ). One possible source of compromised glutamatergic function in SZ is decreased surface expression of GluN2B-containing NMDARs. STEP(61) is a brain-enriched protein tyrosine phosphatase that dephosphorylates a regulatory tyrosine on GluN2B, thereby promoting its internalization. Here, we report that STEP(61) levels are significantly higher in the postmortem anterior cingulate cortex and dorsolateral prefrontal cortex of SZ patients, as well as in mice treated with the psychotomimetics MK-801 and phencyclidine (PCP). Accumulation of STEP(61) after MK-801 treatment is due to a disruption in the ubiquitin proteasome system that normally degrades STEP(61). STEP knockout mice are less sensitive to both the locomotor and cognitive effects of acute and chronic administration of PCP, supporting the functional relevance of increased STEP(61) levels in SZ. In addition, chronic treatment of mice with both typical and atypical antipsychotic medications results in a protein kinase A-mediated phosphorylation and inactivation of STEP(61) and, consequently, increased surface expression of GluN1/GluN2B receptors. Taken together, our findings suggest that STEP(61) accumulation may contribute to the pathophysiology of SZ. Moreover, we show a mechanistic link between neuroleptic treatment, STEP(61) inactivation and increased surface expression of NMDARs, consistent with the glutamate hypothesis of SZ.
[show abstract][hide abstract] ABSTRACT: Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific phosphatase that modulates key signaling molecules involved in synaptic plasticity and neuronal function. Targets include extracellular-regulated kinase 1 and 2 (ERK1/2), stress-activated protein kinase p38 (p38), the Src family tyrosine kinase Fyn, N-methyl-D-aspartate receptors (NMDARs), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). STEP-mediated dephosphorylation of ERK1/2, p38, and Fyn leads to inactivation of these enzymes, whereas STEP-mediated dephosphorylation of surface NMDARs and AMPARs promotes their endocytosis. Accordingly, the current model of STEP function posits that it opposes long-term potentiation and promotes long-term depression. Phosphorylation, cleavage, dimerization, ubiquitination, and local translation all converge to maintain an appropriate balance of STEP in the central nervous system. Accumulating evidence over the past decade indicates that STEP dysregulation contributes to the pathophysiology of several neuropsychiatric disorders, including Alzheimer's disease, schizophrenia, fragile X syndrome, epileptogenesis, alcohol-induced memory loss, Huntington's disease, drug abuse, stroke/ischemia, and inflammatory pain. This comprehensive review discusses STEP expression and regulation and highlights how disrupted STEP function contributes to the pathophysiology of diverse neuropsychiatric disorders.
[show abstract][hide abstract] ABSTRACT: Reduction of Abeta deposition is a major therapeutic strategy in Alzheimer's disease (AD). The concentration of Abeta in the brain is modulated not only by Abeta production but also by its degradation. One of the proteases involved in the degradation of Abeta peptides is endothelin-converting enzyme (ECE). In this study, we investigated the effects of an intracranial administration of a seroptype 5 recombinant adeno-associated viral vector (rAAV) containing the ECE-1 synthetic gene on amyloid deposition in amyloid precursor protein (APP) plus presenilin-1 (PS1) transgenic mice. The rAAV vector was injected unilaterally into the right anterior cortex and hippocampus of 6-month-old mice, while control mice received an AAV vector expressing green fluorescent protein (GFP). Immunohistochemical testing for the hemagglutinin (HA) tag appended to ECE revealed strong expression in areas surrounding the injection sites but minimal expression in the contralateral regions. Immunohistochemical tests showed that Abeta decreases in the anterior cortex and hippocampus in mice receiving the ECE synthetic gene. Further, decreases in Congo red positive deposits were also observed in both regions. These results indicate that increasing the expression of beta-amyloid degrading enzymes through gene therapy is a promising approach to the treatment of AD.
[show abstract][hide abstract] ABSTRACT: Antibodies against the Ass peptide clear Ass deposits when injected intracranially. Deglycosylated antibodies have reduced effector functions compared to their intact counterparts, potentially avoiding immune activation.
Deglycosylated or intact C-terminal specific high affinity anti-Abeta antibody (2H6) were intracranially injected into the right frontal cortex and hippocampus of amyloid precursor protein (APP) transgenic mice. The untreated left hemisphere was used to normalize for the extent of amyloid deposition present in each mouse. Control transgenic mice were injected with an antibody against a drosophila-specific protein (amnesiac). Tissues were examined for brain amyloid deposition and microglial responses 3 days after the injection.
The deglycosylated 2H6 antibody had lower affinity for several murine Fcgamma receptors and human complement than intact 2H6 without a change in affinity for Ass. Immunohistochemistry for Abeta and thioflavine-S staining revealed that both diffuse and compact deposits were reduced by both antibodies. In animals treated with the intact 2H6 antibody, a significant increase in Fcgamma-receptor II/III immunostaining was observed compared to animals treated with the control IgG antibody. No increase in Fcgamma-receptor II/III was found with the deglycosylated 2H6 antibody. Immunostaining for the microglial activation marker CD45 demonstrated a similar trend.
These findings suggest that the deglycosylated 2H6 is capable of removing both compact and diffuse plaques without activating microglia. Thus, antibodies with reduced effector functions may clear amyloid without concomitant immune activation when tested as immunotherapy for Alzheimer's disease.
Journal of Neuroinflammation 02/2006; 3:11. · 4.35 Impact Factor