Dementia with Lewy bodies (DLB) is the second most prevalent neurodegenerative
dementia, where an accumulation of aggregated fibrillar
alpha-synuclein in neurons of limbic and forebrain regions of the brain leads to
visual hallucination,
cognitive impairment of a fluctuating nature and extrapyramidal motor disturbances.
Beta-synuclein counteracts aggregation of
alpha-synuclein in vitro and in animal models, however it is not clear whether this effect occurs in human
Lewy body dementia (LBD) diseases. Here we examine expression of alpha-,
beta-synuclein and autophagy markers in the frontal cortex (BA9) and occipital cortex (BA18-19) of patients with neuropathologically confirmed DLB/LBD and age-matched controls. We provide evidence for neuronal upregulation of
beta-synuclein within the frontal cortex and its decrease in occipital cortex of DLB patients. While
beta-synuclein-containing neurons were consistently devoid of oligomeric
alpha-synuclein in the frontal cortex, we did not observe an overall correlation between total
beta-synuclein and 5G4 levels (marker of oligomeric
alpha-synuclein). The autophagy markers LC3-II and p62 were increased in the areas of
beta-synuclein upregulation in DLB brains, and we show attenuation of autophagy flux when
beta-synuclein is overexpressed in vitro. Altogether, this data suggests that
beta-synuclein changes in DLB may exacerbate neuronal dysfunction caused by accumulation of
alpha-synuclein by influencing protein degradation pathways; this should be taken into consideration when designing therapeutic strategies aimed to decrease
alpha-synuclein burden in Lewy body diseases.