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Abstract
The amyloid-β peptide is considered as a key player in the development and progression of Alzheimer’s disease (AD). Although good evidence exists that amyloid-β accumulates inside cells, intracellular brain amyloid-binding proteins remain poorly characterized. Proteomic profiling of rat brain homogenates, performed in this study, resulted in identification of 89 individual intracellular amyloid-binding proteins, and approximately 25% of them were proteins that we had previously identified as specifically binding to isatin, an endogenous neuroprotector molecule. A significant proportion of the amyloid-binding proteins (more than 30%) are differentially expressed or altered/oxidatively modified in AD patients. Incubation of brain homogenates with 70 µM hydrogen peroxide significantly influenced the profile of amyloid-β binding proteins and 0.1 mM isatin decreased the number of identified amyloid-β binding proteins both in control and hydrogen peroxide treated brain homogenates. The effects of hydrogen peroxide and isatin have been confirmed in optical biosensor experiments with purified glyceraldehyde-3-phosphate dehydrogenase, one of the known crucial amyloid-β binding proteins (also identified in this study). Data obtained suggest that isatin protects crucial intracellular protein targets against amyloid binding, and possibly favors intracellular degradation of this protein via preventing formation of amyloid-β oligomers described in the literature for some isatin derivatives.
Highlights
The amyloid-β peptide 1–42 formed during proteolytic processing of the amyloid precursor protein (APP) is considered as a key player in the development or progression of Alzheimer’s disease (AD)and other pathologies associated with the formation of protein aggregates in the central nervous system ([1,2,3,4,5,6,7,8] and many others)
Subsequent elution of adsorbed proteins followed by their proteomic analysis resulted in identification of at least 89 individual intracellular β-amyloid binding proteins bound to the affinity sorbent (Table S1)
In this study we have investigated profiles of amyloid-binding proteins isolated from control rat brain homogenates and rat brain homogenates treated with hydrogen peroxide, the small non-peptide endogenous regulator isatin, and homogenates treated with hydrogen peroxide in the presence of isatin
Summary
The amyloid-β peptide 1–42 formed during proteolytic processing of the amyloid precursor protein (APP) is considered as a key player in the development or progression of Alzheimer’s disease (AD)and other pathologies associated with the formation of protein aggregates in the central nervous system ([1,2,3,4,5,6,7,8] and many others). Results of experiments on transgenic mice indicate that the intraneuronal amyloid-β accumulation precedes plaque formation [16]. This suggests the importance of amyloid-β interaction with particular intracellular targets. Interaction of amyloid-β with intracellular catalase caused inactivation of this enzyme and accumulation of hydrogen peroxide inside cells [17] This implies that oxidative stress induced in the cells exposed to amyloid-β may be (at least partially) associated with reduced degradation of intracellular hydrogen peroxide [17]
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