Amyloid-Beta Peptides Trigger Aggregation of Alpha-Synuclein In Vitro

Abstract

Alzheimer’s disease (AD) and Parkinson’s disease (PD), including dementia with Lewy bodies (DLB), account for the majority of dementia cases worldwide. Interestingly, a significant number of patients have clinical and neuropathological features of both AD and PD, i.e., the presence of amyloid deposits and Lewy bodies in the neocortex. The identification of α-synuclein peptides in amyloid plaques in DLB brain led to the hypothesis that both peptides mutually interact with each other to facilitate neurodegeneration. In this article, we report the influence of Aβ(1–42) and pGlu-Aβ(3–42) on the aggregation of α-synuclein in vitro. The aggregation of human recombinant α-synuclein was investigated using thioflavin-T fluorescence assay. Fibrils were investigated by means of antibody conjugated immunogold followed by transmission electron microscopy (TEM). Our data demonstrate a significantly increased aggregation propensity of α-synuclein in the presence of minor concentrations of Aβ(1–42) and pGlu-Aβ(3–42) for the first time, but without effect on toxicity on mouse primary neurons. The analysis of the composition of the fibrils by TEM combined with immunogold labeling of the peptides revealed an interaction of α-synuclein and Aβ in vitro, leading to an accelerated fibril formation. The analysis of kinetic data suggests that significantly enhanced nucleus formation accounts for this effect. Additionally, co-occurrence of α-synuclein and Aβ and pGlu-Aβ, respectively, under pathological conditions was confirmed in vivo by double immunofluorescent labelings in brains of aged transgenic mice with amyloid pathology. These observations imply a cross-talk of the amyloid peptides α-synuclein and Aβ species in neurodegeneration. Such effects might be responsible for the co-occurrence of Lewy bodies and plaques in many dementia cases.

Structure and Aggregation Mechanisms in Amyloids

“…In addition, it has also been observed that some amyloidogenic proteins may support cross-seeding by amyloid aggregates of different proteins, building a link between different amyloid forms. Heterologous cross-seeding has been reported between amyloid-β peptide (Aβ) and islet amyloid polypeptide [116,117], Aβ and prion protein (PrP) [118], and Aβ and α-synuclein [119]. Furthermore, Aβ fibrils also induce the formation of tau neurofibrillary tangles in vivo [120], and Aβ aggregates promote tau aggregation in vitro [121].…”

Soluble endogenous oligomeric α-synuclein species in neurodegenerative diseases: Expression, spreading, and cross-talk

“…While many studies have suggested that ␣Syn and A␤ are capable of direct and indirect molecular cross-talks in the brain along with hybrid oligomer formation [21,[174][175][176][177][178][179], few studies have demonstrated that endogenous A␤ and ␣Syn directly interact in cultured cells or in vivo [21]. Specifically, Tsigelny and colleagues reported that ␣Syn and A␤ directly interact in the brains of small (n = 4) groups of patients with AD, DLB and in APP/␣-syn tg mice (Thy1-APPmut tg [line 41] x PDGF␤-␣-syn tg mice [line D]) using co-immunoprecipitation analyses of membrane fractions.…”

Neuropathological Mechanisms Associated with Pesticides in Alzheimer’s Disease

“…Rotenone exposure (as low as 0.5 nM) of neuron cultures from rat hippocampus, substantia nigra and locus coeruleus resulted in the formation of protein aggregates of α-Synuclein and Aβ [56]. Aβ peptides are known to trigger aggregation of α-Synuclein [117], and there is a possibility that heterotypic amyloid co-aggregates could be formed via a α-Synuclein seeding mechanism [118]. Whether such co-aggregations could actually be triggered by any pesticide in cultured neurons or in animal brain remain to be demonstrated.…”