Pathobiological features in neurodegenerative diseases: An overview

Discovery and characterization of fibrillary aggregates composed of specific neuronal/glial proteins in Alzheimer's disease (AD) and other neurodegenerative diseases have not only provided molecular insights into these disorders but also raised mechanistic issues pertaining to the search for the “principal offender” protein in each disease. The pathological hallmarks of AD are neurofibrillary tangles which consist of microtubule-associated protein tau, and senile plaques (SPs) that are composed of amyloid beta peptide (Aβ), respectively. Lewy bodies and Lewy neurites, the characteristic lesions in Parkinson's disease (PD) composed of α-synuclein (α-syn) filaments, also commonly to occur in AD. As frequent and extensive overlap among pathologies with tau, Aβ and α-syn is also observed in diverse neurodegenerative disorders, it is difficult to identify the protein that is the most responsible for the neuropathology in each illness. To address this concern, a great number of transgenic (Tg) mice that over-express one of these proteins/peptides have been generated, and have been demonstrated to show loss of normal functions and gain of neurotoxicity of these molecules with progression of fibrillary pathologies. Moreover, generation of double Tg mice that express two of the above-mentioned molecules do develop enhanced fibrillary lesions relative to single Tg mice, indicating that synergic effects of two or more molecules can greatly contribute to the initiation and promotion of neurodegenerative pathologies.