Parkinson's and Alzheimer's disease as system-wide neurodegenerative disorders

Abstract

Parkinson's and Alzheimer's disease (PD/AD) are characterized by cellular pathological changes that precede clinical manifestation and symptom onset by decades (prodromal period) as well as by aheterogeneity of clinical symptoms. Both diseases are recognized as system-wide diseases with organ-transgressing dysregulation and involvement of immunological and neuroinflammatory mechanisms facilitating pathological protein aggregation and neurodegeneration. Overview of natural course, phenotypes and classification of PD/AD with afocus on underlying (system-wide) immunological and neuroinflammatory mechanisms. Literature research and consideration of expert opinions. The accumulation of misfolded proteins such as amyloid‑β and synuclein in the course of neurodegenerative processes forms the basis of the current biological classifications, understanding of course and subtypes. Protein aggregation in PD/AD induces an innate immune response by activating microglia and the release of inflammatory mediators such as cytokines and chemokines and leading to further spread of neurodegeneration and accumulation of intracellular neurofibrillary tangles (NFTs). There is also growing evidence that adaptive immune responses involving auto-antibodies or auto-antigen-specific T‑/B-cell reactions involving tau, amyloid‑β or synuclein might be involved in the disease progression or subtypes of PD/AD. Both innate and adaptive immune responses seem to be substantially involved in the pathological cascade leading to neurodegeneration in PD/AD and may contribute to disease progression and clinical subtypes. Thus, future targeted interventions should not only focus on protein aggregation but also on neuroinflammatory and immunological mechanisms.