Alzheimer's Disease: From Pathology to Therapeutic Approaches

Abstract

Mind how you go: The current strategies for the development of therapies for Alzheimer's disease are very diverse. Particular attention is given to the search for inhibitors (see picture for two examples) of the proteolytic enzyme beta- and gamma-secretase, which inhibits the cleavage of the amyloid precursor proteins into amyloid beta peptides, from which the disease-defining deposits of plaque in the brains of Alzheimer's patients originates.Research on senile dementia and Alzheimer's disease covers an extremely broad range of scientific activities. At the recent international meeting of the Alzheimer's Association (ICAD 2008, Chicago) more than 2200 individual scientific contributions were presented. The aim of this Review is to give an overview of the field and to outline its main areas, starting from behavioral abnormalities and visible pathological findings and then focusing on the molecular details of the pathology. The "amyloid hypothesis" of Alzheimer's disease is given particular attention, since the majority of the ongoing therapeutic approaches are based on its theoretical framework.

Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

“…brillary tangles (A␤ 25/26 -35 ) and in the degenerating hippocampal CA1 neurons with intracellular neurofibrillary tangles (A␤ [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] ), in AD brains, but not in agematched control subjects. 15 Deposits of A␤ [25][26][27][28][29][30][31][32][33][34][35] peptide after its injection have not yet been characterized by IHC, for lack of specific and selective antibodies.…”

“…34 -36 This pattern is, however, consistent with hippocampus damage observed in AD brains. 37,38 Amyloid toxicity directly affects neuronal physiology, particularly the cholinergic system. After 8 days, A␤ [25][26][27][28][29][30][31][32][33][34][35] injection decreased choline acetyltransferase activity in the medial septum, cortex, and hippocampus and decreased the number of choline acetyltransferase-immunoreactive cells in the medial septum.…”

“…The cholinergic deficits induced by A␤ [25][26][27][28][29][30][31][32][33][34][35] injection therefore appear to be in accord with the well-characterized pathological hallmarks described in AD. 37,38 Oxidative stress contributed to the in vivo A␤-induced toxicity. At 1 week after injection, A␤ [25][26][27][28][29][30][31][32][33][34][35] induced significant oxidative stress in the hippocampus, as reflected by measured increases in lipid peroxidation, protein nitration, and superoxide generation.…”

Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

“…Approaches that target the underlying mechanisms of proteotoxicity are currently in the developmental stage, i.e., under clinical or preclinical evaluation [47,48]. Recent studies involving natural compounds have suggested intervention strategies that target the protein misfolding cascade in new ways.…”

Dieta mediterránea y sus efectos benéficos en la prevención de la enfermedad de Alzheimer

“…La placa neurítica es una estructura esférica que contiene Ab rodeada por neuritas distróficas, proteoglicanos, Apoe 4 , antiquimiotripsina a 1 y otras proteínas 4,[6][7][8][9][10][11] .…”