. Inhibition of amyloid-β plaque formation by α-synuclein. Nat Med. 2015 Jul;21(7):802-7. Epub 2015 Jun 22 PubMed.


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  1. The in vivo experiments demonstrate quite clearly that not only does α-synuclein not enhance Aβ deposition, but actually inhibits it. This is somewhat counterintuitive and quite interesting given that Aβ and α-synuclein pathology frequently co-occur in human disease. It also raises the question of where such an interaction would occur, given that one is mainly an extracellular peptide while the other intracellular. The in vitro experiments point toward their interacting as monomers/oligomers and it will be interesting to see if the hybrid oligomers postulated by the authors are indeed a highly toxic species.

    View all comments by Kelvin Luk
  2. This is an intriguing study. Already in 2007, Hui Zheng and colleagues (Kallhoff et al., 2007) showed that the lack of α-synuclein reduced plaque pathology and increased synaptophysin levels in Aβ transgenic mouse brains. Now, Bachhuber and colleagues have performed a series of intelligent in vitro and in vivo studies to further elucidate the interplay between Aβ and α-synuclein. Taken together, their data suggest that various forms of these molecules may form co-deposits that prevent fibril formation and increase neurotoxicity in the brains of transgenic mice. However, since the intracerebral injections of α-synuclein-containing samples were performed bilaterally, we don’t know if global seeding effects also occurred. Given the recent studies demonstrating contralateral propagation of α-synuclein, more far-reaching intermolecular seeding effects could indeed be possible.


    . Lack of alpha-synuclein increases amyloid plaque accumulation in a transgenic mouse model of Alzheimer's disease. Mol Neurodegener. 2007;2:6. PubMed.

    View all comments by Martin Ingelsson
  3. Little is known about the mutual trajectories of α-synuclein and Aβ accumulation in vivo in humans. Longitudinal imaging studies do not yet exist. We recently examined the clinical phenotype (cognitive fluctuation, recurrent visual hallucinations, parkinsonism, and REM sleep behavior disorder) in 64 autopsy-confirmed cases of dementia with Lewy bodies (DLB). Neocortical Aβ deposits were quantified using the BA4 antibody. Each brain was also staged for the degree of neuritic plaque pathology according to CERAD criteria using the Gallyas silver technique, and for the degree of neurofibrillary tangle pathology by the Braak method using the AT8 antibody. Lower frequencies of core clinical features of DLB, resulting in lower accuracy of its clinical diagnosis, were associated with decreasing Lewy body distribution (p < 0.0001) and with increasing neuritic plaque pathology (p = 0.035), but not with the number of Aβ plaque deposits (Tiraboschi et al., 2015). We concluded that the molecular relationship between LB- and AD-type pathology remains obscure. It may be that Aβ deposition is the primary event in both AD and DLB and that preferential downstream effects are either tau aggregation, resulting in a clinical phenotype more like that of AD, or α-synuclein aggregation, resulting in a clinical phenotype more like that of DLB. In some individuals, these overlapping pathologies result in an ambiguous clinical profile.

    This report by Bachhuber and colleagues of synuclein inhibiting amyloid deposition is not immediately compatible with this model, nor with the fact that when amyloid is seen in DLB cases (about 50 percent of the time) using in vivo brain PET, levels are generally in the AD range. Why amyloid is deposited in some, but not all DLB cases remains unanswered.


    . Clinicians' ability to diagnose dementia with Lewy bodies is not affected by β-amyloid load. Neurology. 2015 Feb 3;84(5):496-9. Epub 2014 Dec 31 PubMed.

    View all comments by Ian McKeith

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  1. Alpha-Synuclein Stymies Amyloid Plaques, but Worsens Synaptic Damage