Human amyloid beta and a-synuclein co-expression in neurons impair behavior and recapitulate features for Lewy body dementia in Caenorhabditis elegans

Amyloid beta (A beta), a product of APP, and SNCA (alpha-synuclein (alpha-syn)) are two of the key proteins found in lesions associated with the age-related neurodegenerative disorders Alzheimer's disease (AD) and Parkinson's disease (PD), respectively. Previous clinical studies uncovered A beta and alpha-syn co-expression in the brains of patients, which lead to Lewy body dementia (LBD), a disease encompassing Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). To explore the pathogenesis and define the relationship between A beta and alpha-syn for LBD, we established a C. elegans model which co-expresses human A beta and alpha-syn with alanine 53 to threonine mutant (alpha-syn(A53T)) in pan-neurons. Compared to alpha-syn(A53T) single transgenic animals, pan-neuronal A beta and a-syn (A53T) co-expression further enhanced the thrashing, egg laying, serotonin and cholinergic signaling deficits, and dopaminergic neuron damage in C. elegans. In addition, A beta increased alpha-syn expression in transgenic animals. Transcriptome analysis of both A beta;alpha-syn(A53T) strains and DLB patients showed common downregulation in lipid metabolism and lysosome function genes, suggesting that a decrease of lysosome function may reduce the clearance ability in DLB, and this may lead to the further pathogenic protein accumulation. These findings suggest that our model can recapitulate some features in LBD and provides a mechanism by which A beta may exacerbate alpha-syn pathogenesis.

Automated summary

The study found that the co-expression of A beta and alpha-synuclein in the brains of patients with Lewy body dementia may exacerbate the pathogenic process. The experimental results showed that co-expression of A beta and alpha-syn (A53T) in C. elegans further aggravated movement, egg laying, signaling deficits, and dopaminergic neuron damage. These findings suggest a potential mechanism by which A beta may enhance alpha-syn pathogenesis in Lewy body dementia.