The amyloid hypothesis of Alzheimer's disease: Past and present, hopes and disappointments

Abstract

In 1887, S.A. Belyakov, a physician of the Imperial Medical and Surgical Academy, first described amyloid deposits in the brain of patients with dementia. Later, in 1906, A. Alzheimer revealed amyloid plaques and tau tangles in a patient with clinical signs of dementia. Over the following 100 years, the development of the concept of the amyloid origin of Alzheimer's disease (AD) confirmed numerous relationships between the brain accumulation of APs and cognitive decline. And if at the beginning of the amyloid era many researchers considered that the disease was caused by amyloid beta (Aβ) protein overproduction, in recent years they have increasingly pointed to a defect in the mechanisms of Aβ clearance, especially after the discovery of the lymphatic system of the brain. The role of disturbed homeostasis of redox-active metals, primarily iron and copper, in the development of the disease is also considered. The amyloid hypothesis of AD has served as the basis for several areas in the design of drugs, such as secretase inhibitors, immunomodulatory drugs for active and passive immunization. However, only one drug (Akatinol memantine, an inhibitor of NMDA receptors and glutamatergic excitotoxicity) for the treatment of AD has been introduced into clinical practice over the past 20 years. Of interest are the data obtained in new studies of Akatinol memantine, which suggest that the latter is able to some extent affect the main pathophysiological processes underlying the development of cognitive impairment in Alzheimer-type pathology.