4 December 2006. Dementia strikes in many forms besides Alzheimer disease, and two recent reports take a look at the biochemical basis for dementias in other settings. One paper, from the lab of Christopher Power, University of Alberta, Edmonton, shows that proteolytic processing of a cytokine produces a peptide with retooled receptor binding specificity. This processing converts the cytokine from helpful to harmful, as the truncated form causes neurotoxicity via the G protein-coupled receptor (GPCR) CXCR3. In the other paper, Eugenia Gurevich and coworkers at Vanderbilt University Medical Center in Nashville, Tennessee, report changes in the proteins that regulate GPCRs are specific to Parkinson disease patients with dementia, and not those without. This is the same subset of PD patients who often show resistance to L-dopa treatment.
The cytokine story, which is reminiscent of the proteolysis processing of amyloid precursor to toxic Aβ, starts with the activation of HIV-infected immune cells in the brain. These cells produce inflammatory mediators, including cytokines. Previously, Power and colleague Christopher Overall, University of Vancouver, British Columbia, showed that cleavage of the chemokine stromal cell-derived factor (SDF)1α by matrix metalloprotease 2 in activated monocytic cells produces a truncated, neurotoxic peptide product, SDF(5-67). Their new work, published online in last week’s PNAS, shows that the neurodegenerative properties of SDF(5-67) stem from an altered receptor binding specificity.
Although an SDF(5-67) fragment has been implicated in dementia associated with HIV, no one had ever measured the peptide in the brain, so lead author David Vergote of the Power lab and colleagues checked the brain tissue of four HIV-infected patients, two with and two without dementia. They found elevated SDF1α and SDF(5-67) in all the HIV-positive tissue compared with negative controls, with the highest amounts in the two patients with dementia. Immunoreactivity to SDF(5-67) occurred in macrophage/microglial cells, which also expressed MMP-2.
Having established that SDF(5-67) is, in fact, present in brain of people infected with HIV, the researchers took a closer look at its effects on different cells in vitro. They found that the SDF(5-67) fragment induced inflammatory genes in monocytes or astrocytes. In neurons, the peptide depressed whole cell currents and triggered caspase-3 and p53-dependent cell death. The parent peptide had none of these effects.
Intact SDF-1α binds to the chemokine receptor CXCR4, but the truncated peptide does not. It does, however, have affinity for CXCR3, and the authors showed that the peptide bound to this receptor on cultured cells. Blocking the interaction on neurons with anti-receptor antibodies, an antagonist peptide, or siRNA to the receptor prevented SDF(5-67)-induced neurotoxicity. In vivo, they used a mouse model of AIDS dementia, involving injection of SDF(5-67) directly into the striatum, to show that blocking CXCR3 with a receptor antagonist peptide prevented astrogliosis, microgliosis, neuronal loss, and behavioral problems. The peptide may do its damage both by direct toxicity and by indirect incitement of neuroinflammation, and the results suggest both of these effects are mediated by the switch in binding specificity to CXCR3.
Parkinson disease can also feature dementia in about 30-40 percent of patients as the disease progresses. The paper by Gurevich and colleagues, published in the Neurobiology of Aging online on November 27, shows that PD patients with dementia have distinct biochemical changes in the striatum compared to healthy controls or PD patients with no dementia. Working with Jeff Joyce at the Sun Health Research Institute, Sun City, Arizona, first author Evgeny Bychkov and colleagues establish that postmortem tissue from only this subset of patients displays increases in the protein and messenger RNAs for regulators of GPCRs, namely the arrestins and G protein-coupled receptor kinases (GRKs).
Arrestins uncouple GPCRs from downstream signaling molecules and can enhance their degradation; GRKs also modulate the signaling activity of GPCRs. To look for changes in these pathways, the authors collected postmortem brain samples from 21 patients with PD and 16 normal controls. Western blotting and RNase protection assays showed that the protein and messenger RNAs for arrestins 2 and 3, and GRKs 3 and 5, were elevated up to twofold in the striatum in the subset of Parkinson patients with dementia, but not in those without, or in control brains. Because arrestins not only uncouple GPCRs from G proteins, but also stimulate specific signaling pathways when they associate with the receptors, the researchers checked the protein levels of the secondary signaling molecules Erk, Akt, and GSK3, and found each was increased in the Parkinson with dementia group. In contrast, the dopamine receptor regulator DAARP-32 was not.
Dementia in PD sometimes comes along with amyloid plaques and neurofibrillary tangles, but the changes in signaling proteins were not related to the presence of this kind of pathology. Thus, the changes seemed specific for dementia, though more studies with larger samples will be necessary to confirm this.
Increases in arrestins/GRKs dampen GPCR signaling, so one might predict they would be decreased in PD as compensation for lower dopamine levels. The researchers did see some trend toward downregulation of the proteins in PD, but this situation was clearly reversed in PD with dementia. Consistent with this, the same group has previously reported that the dopamine receptor is downregulated in PD with dementia (Joyce et al., 2002).
PD with dementia is associated with loss of response of Parkinson symptoms to L-dopa. Based on this data, and their previous studies with nonhuman primates, the authors speculate that in patients who are sensitive to L-dopa, the drug may act via dopamine receptors to keep arrestin/GRK levels down. However, if patients have persistently elevated levels of arrestins/GRKs, they could end up with drug resistance via downregulation of DA receptors, and dementia via perturbation of multiple signaling mechanisms.—Pat McCaffrey.
Bychkov ER, Gurevich VV, Joyce JN, Benovic JL, Gurevich EV. Arrestins and two receptor kinases are upregulated in Parkinson's disease with dementia. Neurobiol Aging. 2006 Nov 22; [Epub ahead of print] Abstract
Vergote D, Butler GS, Ooms M, Cox JH, Silva C, Hollenberg MD, Jhamandas JH, Overall CM, Power C. Proteolytic processing of SDF-1alpha reveals a receptor specificity mediating HIV-associated neurodegeneration. PNAS. 2006 Dec 4; [Epub ahead of print] Abstract