Colocalization of Tau and Alpha-Synuclein Epitopes in Lewy Bodies

Abstract

The major protein constituent of Lewy bodies (LBs), the pathological hallmark of Parkinson disease and dementia with Lewy bodies, is considered to be alpha-synuclein, but other proteins, in particular the microtubule-associated protein tau, have been implicated in the pathogenesis of LBs. Tau is the major structural component of neurofibrillary tangles (NFTs). Both direct immunochemical studies of partially purified LBs and indirect immunohistochemical studies have suggested that LBs may contain tau, but most of these studies were based upon a single tau antibody, and immunologic cross-reactivity was not completely excluded. To gain insight into the relation between tau and alpha-synuclein in LBs, double immunostaining was performed in Lewy body cases with a rabbit polyclonal antibody to alpha-synuclein and a panel of monoclonal antibodies to phospho- and nonphospho-tau epitopes (Alz50, CP9, CP13, PG5, TG3, PHFI) that spanned the length of the tau molecule. Tau-immunoreactive LBs were present in the medulla in 80% of the cases, irrespective of Braak stage. All tau antibodies recognized at least some LBs, arguing against nonspecific antibody cross-reactivity. In most lesions the tau immunostaining was present at the periphery of the LB. The phospho-tau antibody, TG3, detected more LBs than any of the other tau antibodies. The proportion of LBs with tau immunoreactivity was greatest in neurons vulnerable to NETs, such as those in the locus ceruleus and basal nucleus of Meynert, and least in neurons resistant to NFTs, such as the dorsal motor nucleus of the vagus in the medulla. The present results suggest that tau may coaggregate with alpha-synuclein in LBs, especially in neuronal populations vulnerable to both NFTs and LBs.

Amyloid-β deposition and regional grey matter atrophy rates in dementia with Lewy bodies

“…Higher burden of both -synuclein (Duda et al, 2002a;Jellinger and Attems, 2006) and amyloid-b deposition (Jellinger and Attems, 2006;Edison et al, 2008;Kalaitzakis et al, 2008) has been observed in the striatum of patients with DLB, suggesting a possible interaction between -synuclein and amyloid-b aggregation. Furthermore, tau and -synuclein deposits may be aggregating topographically in close proximity in synucleinopathies (Duda et al, 2002b;Ishizawa et al, 2003;Kotzbauer et al, 2004), supporting direct cross-seeding between the two types of pathologies (Guo et al, 2013), which could influence striatal degeneration in DLB patients.…”

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

“…Furthermore, as these proteins may co-aggregate and/or regulate each other [29,30,[159][160][161], immunization against one of them could reduce the aggregation or toxic modification of the others. For example, immunization against Aβ might be helpful at reducing α-syn and tau if administered at early disease stages [62]; likewise, α-syn antibodies might also be helpful in AD [162], and immunization against tau might be useful for PD [161,163]. In this sense, identifying and targeting polyvalent antigens or using single-chain polyvalent antibodies targeting simultaneously Aβ, tau, and α-syn could have synergistic effects, as it occurs with polyvalent vaccines for certain cancers and infections [164,165].…”

Tau gene transfer, but not alpha-synuclein, induces both progressive dopamine neuron degeneration and rotational behavior in the rat

“…The P301L FTDP-17-related form of tau is particularly pathogenic as it exhibits accelerated filament formation in vitro (Nacharaju et al, 1999) and transgenic mice expressing P301L tau develop neurofibrillary tangles (NFTs; Lewis et al, 2000). While idiopathic PD is not associated with NFTs, tau has been demonstrated in a subpopulation of Lewy bodies (Ishizawa et al, 2003). Using a viral vector for P301L tau, we previously developed a rat model for NFT formation in the basal forebrain (Klein et al, 2004).…”