PART 4: Like DLB, Like AD -- Do Oligomers Stir Up the ...

PART 4: Like DLB, Like AD -- Do Oligomers Stir Up the Trouble?

2 June 2009. Current work on distinguishing Alzheimer disease from its cousin dementia with Lewy bodies (DLB, see Part 3 of this series) has underscored one intriguing similarity between the two. In DLB, researchers increasingly note that many people, indeed up to half in some patient series, remain neurologically intact despite having abundant Lewy body pathology in their brains. In AD, florid amyloid pathology in the brains of people who died cognitively normal has for years sustained doubt about the amyloid hypothesis. In DLB now as formerly in AD, the pathologic observation raises questions about whether Lewy bodies are toxic or even relatively protective compared with even more toxic oligomeric aggregates of α-synuclein that remain invisible to the stains typically used on brain slices.

At the Kassel workshop preceding the 9th International Conference AD/PD, Laura Parkkinen of the Institute of Neurology, London, UK, broached this issue in a clinico-pathological talk. Similarly, Walther Schulz-Schaeffer of the University of Goettingen, Germany, proposed that not Lewy bodies, but smaller α-synuclein aggregates at synapses, are the real culprits (Kramer and Schulz-Schaeffer et al., 2007; Kramer et al., 2008). And at AD/PD in Prague, Maria-Grazia Spillantini of Cambridge University, UK, previewed data from a new mouse model of α-synucleinopathy that pinned early pathogenic changes on mislocalization of monomeric α-synuclein within presynaptic terminals (see also Watson et al., 2009). Spillantini proposed that the neurons seen laden with Lewy bodies in autopsy tissue might represent those cells that were the latest to have gotten sick, i.e., that have withstood a disease process driven by smaller assemblies.

Mice are also the model of choice to try to understand whether different pathogenic proteins interact, perhaps as oligomers, before they form their signature microscopic deposits. Eliezer Masliah of the University of California, San Diego, has for some time explored molecular interactions between Aβ and α-synuclein, showing first that Aβ potentiates the deposition of α-synuclein in transgenic mice (Masliah et al., 2001) and more recently that these two proteins can form mixed ring-like oligomers in membranes (Tsigelny et al., 2008 on ARF related news story). In Kassel and in Prague, Masliah expanded on the theme. He introduced several different unpublished mouse systems that combine transgenic lines and lentiviral injection. Together, these build a body of data suggesting that Aβ42 promotes α-synuclein aggregation, worsens learning deficits, and can drive neurodegeneration in these mixed models. This happens regardless of whether APP is added to an α-synuclein transgenic background or α-synuclein is added to an APP-transgenic background.

Most likely, Aβ is upstream of α-synuclein, researchers agreed. This creates a parallel with older Alzheimer's research placing Aβ upstream of tau, and it puts α-synuclein and tau on a par in a sense. Expressed in mice, the mutant human tau that causes frontotemporal dementia leads to tangles and a behavioral phenotype mostly in the spinal cord (Lewis et al., 2000), but when these mice cross-breed with APP transgenic mice, the Aβ in the resulting offspring greatly amplifies tau pathology in the cortex (Lewis et al., 2001; also Goetz et al., 2001). The idea is that, similarly, the co-occurrence of Aβ might help α-synuclein pathology spread in the human brain.

“The idea of one pathology augmenting another is accepted in AD, and now comes up in DLB, as well,” noted John Hardy of University College, London, UK. Other scientists agreed that amyloid pathology probably deposits first in people, before inciting either tau or α-synuclein pathology. More than two pathogenic proteins can be at play, as some scientists suspect tau heating up α-synuclein pathology downstream of amyloid. “In the mixed pathologies, we know that amyloid deposits first. Then there occurs some unknown step that we need to understand much better,” said Galvin.

This point drew wide notice in Prague. “Broadly, the idea that one of those proteins can influence aggregation of another is gaining prominence,” said Charles Glabe of University of California, Irvine, who mentioned collaborative work with a German group indicating that therapeutic removal of amyloid can draw down α-synuclein inside cells. “The big question is how that happens, whether directly at the membrane or through activating autophagy.”

Interaction between Aβ and α-synuclein might imply that upstream (read anti-amyloid) therapies might benefit downstream α-synuclein pathology (read DLB patients), as well. Masliah showed data suggesting that anti-Aβ immunotherapies treat synucleinopathy and attendant functional deficits quite nicely in transgenic mice. Alas, the known trials and tribulations of translating mouse treatments to humans apply. Other scientists cautioned that diseases marked in large part by pathologies downstream of Aβ amyloid might at some point become independent of that amyloid once disease is established, such that removing the initial offender no longer helps the patient very much because it leaves in place an active tauopathy or synucleinopathy.

Antibodies against α-synuclein are under construction in Masliah's laboratory. In Prague, Brian Spencer in Masliah's lab presented a poster showing a lentivirus single-chain antibody against α-synuclein oligomers. When injected into the brain of α-synuclein transgenic mice, the antibody rescued neurodegeneration in these animals. The mechanism, Masliah believes, is not so much microglial clearance but activation of the autophagy pathway of protein degradation. This, if it could be revved up safely, might just offer a new therapy development avenue to pursue against both AD and DLB. -- Gabrielle Strobel.

ARF related news story: http://www.alzforum.org/new/detail.asp?id=1920

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Kramer ML, Schulz-Schaeffer WJ. Presynaptic alpha-synuclein aggregates, not Lewy bodies, cause neurodegeneration in dementia with Lewy bodies. J Neurosci. 2007 Feb 7;27(6):1405-10.

Kramer ML, Behrens C, Schulz-Schaeffer WJ. Selective detection, quantification, and subcellular location of alpha-synuclein aggregates with a protein aggregate filtration assay. Biotechniques. 2008 Mar;44(3):403-11.

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Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, Sahara N, Skipper L, Yager D, Eckman C, Hardy J, Hutton M, McGowan E. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science. 2001 Aug 24;293(5534):1487-91.

Masliah E, Rockenstein E, Veinbergs I, Sagara Y, Mallory M, Hashimoto M, Mucke L. beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease. Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12245-50.

Tsigelny IF, Crews L, Desplats P, Shaked GM, Sharikov Y, Mizuno H, Spencer B, Rockenstein E, Trejo M, Platoshyn O, Yuan JX, Masliah E. Mechanisms of hybrid oligomer formation in the pathogenesis of combined Alzheimer's and Parkinson's diseases. PLoS ONE. 2008;3(9):e3135.

Watson JB, Hatami A, David H, Masliah E, Roberts K, Evans CE, Levine MS. Alterations in corticostriatal synaptic plasticity in mice overexpressing human alpha-synuclein. Neuroscience. 2009 Mar 17;159(2):501-13.

This is Part 4 of a nine-part series. See also Part 1, Part 2, Part 3, Part 5, Part 6, Part 7, Part 8, Part 9.