M.Yu. Stepanichev, N.V. Gulyaeva
Alzheimer’s disease (AD) is neurodegenerative disorder associated with dementia, which is mani-fested in the late age. AD is associated with neuronal death mostly expressed in populations of cholinergic neurons. However, mechanisms of neuronal death remain to be obscure. One of the central events in AD pathogenesis is excessive accumulation of amyloid-β peptide (Aβ) in the brain tissue. Aβ consists of 40-42 amino acids. There are two principal ways leading in an excess of Aβ in the brain: 1) impairments of metabolism of the amyloid precursor protein; 2) impairments of Aβ proteolysis. The peptide can form fibrils with toxic effects for brain cells, and may be deposited in the tissue as insoluble plaques. Several laboratories have demonstrated that during aging, race-mization of Aβ takes place in senile plaques. Substitution of L-serine in the 26th residue for D-serine results in solubility of this protein and makes it available for proteolysis by endogenous brain proteases. After this, a shorter peptide [D-Ser26] Aβ(25/26-35) is formed. It is capable more rapidly to form small cell permeable aggregates, which are more toxic as compared to the maternal peptide. Aβ including an 11-amino-acid peptide Aβ(25-35) may be used for modeling of AD at laboratories. Administration of Aβ(25-35) into rodent brain results in impairments of memory and death of neurons in brain regions playing an important role in cognitive processes. Interestingly, short-term memory is more vulnerable to Aβ whereas long-term memory remains to be more tol-erant. Memory impairments observed after injection of Aβ(25-35) may be a consequence of Aβ(25-35)-induced cholinergic deficit or cell death in the hippocampus and neocortex. Among the mech-anisms mediating neuronal death after application of Aβ(25-35) we can primarily indicate oxidative stress-related processes, i.e. excessive generation and/or impaired elimination of active forms of oxygen and nitrogen. Thus, studies of processes underlying effects of Aβ(25-35) in animal brain allow to reproduce specific features of AD pathogenesis. Analysis of data on in vivo studies show that an 11-amino-acid peptide Aβ(25-35) is one of the crucial players in a pathogenetic AD cascade. Models based on application of Aβ(25-35) are very promising for investigation of AD pathogenetic mechanisms related to amyloid toxicity.