Abstract
β-amyloid hypothesis is the predominant hypothesis in the study of pathogenesis of Alzheimer's disease. This hypothesis claims that aggregation and neurotoxic effects of amyloid β (Aβ) is the common pathway in a variety of etiological factors for Alzheimer's disease. Aβ peptide derives from amyloid precursor protein (APP). β-sheet breaker peptides can directly prevent and reverse protein misfolding and aggregation in conformational disorders. Based on the stereochemical structure of Aβ1-42 and aggregation character, we had designed a series of β-sheet breaker peptides in our previous work and screened out a 10-residue peptide β-sheet breaker peptide, H102. We evaluated the effects of H102 on expression of P-tau, several associated proteins, inflammatory factors and apoptosis factors, and examined the cognitive ability of APP transgenic mice by behavioral test. This study aims to validate the β-amyloid hypothesis and provide an experimental evidence for the feasibility of H102 treatment for Alzheimer's disease.
Highlights
Alzheimer’s disease (AD) is a major progressive neurodegenerative disorder in the central nervous system, a hallmark event is the misfolding and aggregation of an otherwise normal protein [1,2,3]
We demonstrated the inhibitory action of H102 on amyloid b (Ab) aggregation [23], its positive effects on Ab degradation [24] and the expression of the proteins [25] of synaptophysin, PSD-95 and Shank-1, which were identified to be involved in the rehabilitation of nerve synapse [26] as well as the effects of acetylcholine in the nervous system (ChAT, AChE) and free radicals (MDA and Superoxide dismutase (SOD)) [27].This study aims to clarify the effects of H102 on inflammatory factors, P-tau and several associated proteins, apoptosis factors and behavioral changes
According to the amyloid hypothesis, aggregation of Ab in the brain plays a primary role in the pathogenesis of AD [9]
Summary
Alzheimer’s disease (AD) is a major progressive neurodegenerative disorder in the central nervous system, a hallmark event is the misfolding and aggregation of an otherwise normal protein [1,2,3]. The correlation between the diffusion of amyloid plaques in the brain and the progression of the disease remains controversial [11,12], the amyloid hypothesis has been investigated as a predominant hypothesis in the study of pathogenesis of AD [9] This hypothesis claimed that Ab aggregation initiates the disease processes of AD, which involve the effects of acetylcholine in the nervous system, damage of synaptic plasticity, formation of free radicals, disequilibrium of intracellular calcium ion distribution, chronic inflammation, excessive phosphorylation of P-tau and other physiopathologic changes. These factors induce cell apoptosis and produce a series of clinical symptoms, including neuron death, memory lapse, cognitive ability decrease, behavior disorders and so on. Aggregation of Ab plays a key role and is an initial factor for the pathogenesis of AD, and Ab-based interventional therapy becomes an important research area in treatment of AD
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