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Amyloid-β (Aβ) plaques and α-synuclein (α-syn)-rich Lewy bodies are the major neuropathological hallmarks of Alzheimer's disease (AD) and Parkinson's disease, respectively. An overlap of pathologies is found in most individuals with dementia with Lewy bodies (DLB) and in more than 50% of AD cases. Their brains display substantial α-syn accumulation not only in Lewy bodies, but also in dystrophic neurites decorating Aβ plaques. Several studies report binding and coaggregation of Aβ and α-syn, yet the precise role of α-syn in amyloid plaque formation remains elusive. Here we performed intracerebral injections of α-syn-containing preparations into amyloid precursor protein (APP) transgenic mice (expressing APP695(KM670/671NL) and PSEN1(L166P) under the control of the neuron-specific Thy-1 promoter; referred to here as 'APPPS1'). Unexpectedly, α-syn failed to cross-seed Aβ plaques in vivo, but rather it inhibited plaque formation in APPPS1 mice coexpressing SNCA(A30P) (referred to here as 'APPPS1 × [A30P]aSYN' double-transgenic mice). This was accompanied by increased Aβ levels in cerebrospinal fluid despite unchanged overall Aβ levels. Notably, the seeding activity of Aβ-containing brain homogenates was considerably reduced by α-syn, and Aβ deposition was suppressed in grafted tissue from [A30P]aSYN transgenic mice. Thus, we conclude that an interaction between Aβ and α-syn leads to inhibition of Aβ deposition and to reduced plaque formation.