Up-regulation of matrix metallopeptidase 12 in motor neurons undergoing synaptic stripping.

Axotomy of the rodent facial nerve represents a well-established model of synaptic plasticity. Post-traumatic "synaptic stripping" was originally discovered in this system. We report upregulation of matrix metalloproteinase MMP12 in regenerating motor neurons of the mouse and rat facial nucleus. Matrix metalloproteinases (matrix metallopeptidases, MMPs) are zinc-binding proteases capable of degrading components of the extracellular matrix and of regulating extracellular signaling networks including within synapses. MMP12 protein expression in facial motor neurons was enhanced following axotomy and peaked at day 3 after the operation. The peak of neuronal MMP12 expression preceded the peak of experimentally induced synaptic plasticity. At the same time, MMP12 redistributed intracellularly and became predominantly localized beneath the neuronal somatic cytoplasmic membrane. Both findings point to a role of MMP12 in the neuronal initiation of the synaptic stripping process. MMP12 is the first candidate molecule for such a trigger function and has potential as a therapeutic target. Moreover, since statins have been shown to increase the expression of MMP12, interference with synaptic stability may represent one mechanism by which these widely used drugs exert their side effects on higher CNS functions.

The potential for genetically altered microglia to influence glioma treatment.

Diffuse and unstoppable infiltration of brain and spinal cord tissue by neoplastic glial cells is the single most important therapeutic problem posed by the common glioma group of tumors: astrocytoma, oligoastrocytoma, oligodendroglioma, their malignant variants and glioblastoma. These neoplasms account for more than two thirds of all malignant central nervous system tumors. However, most glioma research focuses on an examination of the tumor cells rather than on host-specific, tumor micro-environmental cells and factors. This can explain why existing diffuse glioma therapies fail and why these tumors have remained incurable. Thus, there is a great need for innovation. We describe a novel strategy for the development of a more effective treatment of diffuse glioma. Our approach centers on gaining control over the behavior of the microglia, the defense cells of the CNS, which are manipulated by malignant glioma and support its growth. Armoring microglia against the influences from glioma is one of our research goals. We further discuss how microglia precursors may be genetically enhanced to track down infiltrating glioma cells.

CSF BACE1 activity is increased in CJD and Alzheimer disease versus [corrected] other dementias.

To assess the diagnostic utility of CSF BACE1 activity for discriminating Alzheimer disease (AD) from other dementias, particularly Creutzfeldt-Jakob disease (CJD), the authors studied 26 patients with sporadic CJD, 21 patients with AD, and 21 patients with various non-AD, non-CJD dementias (DCs). CSF BACE1 activity was elevated in AD in comparison with DC (p = 0.01). Unexpectedly, CSF BACE1 activity was also increased in sporadic CJD (p = 0.02).

Neurotrophic factors and Alzheimer's disease: are we focusing on the wrong molecule?

Brain derived neurotrophic factor (BDNF) promotes cholinergic neuron function and survival. In Alzheimer's disease, BDNF mRNA and protein are decreased in basal forebrain cholinergic neuron target tissues such as cortex and hippocampus. Using RT-PCR, we demonstrate that BDNF is synthesized in basal forebrain, supplying cholinergic neurons with a local as well as a target-derived source of this factor. BDNF mRNA levels are decreased 50% in nucleus basalis of Alzheimer disease patients compared to controls. Thus, not only do the basal forebrain cholinergic neurons have a reduced supply of target-derived BDNF, but also of local BDNF. We also show by Western blotting that human CNS tissue contains both proBDNF and mature BDNF protein. Moreover, we demonstrate a significant (2.25-fold) deficit in proBDNF protein in Alzheimer's disease parietal cortex compared to controls. Thus, reduced BDNF mRNA and protein levels in Alzheimer's disease suggests that BDNF administration may be an effective therapeutic strategy for this disorder.