Parkinson's disease dementia: convergence of α-synuclein, tau and amyloid-β pathologies

Abstract

Dementia is increasingly being recognized in cases of Parkinson's disease (PD); such cases are termed PD dementia (PDD). The spread of fibrillar α-synuclein (α-syn) pathology from the brainstem to limbic and neocortical structures seems to be the strongest neuropathological correlate of emerging dementia in PD. In addition, up to 50% of patients with PDD also develop sufficient amyloid-β plaques and tau-containing neurofibrillary tangles for a secondary diagnosis of Alzheimer's disease (AD), and these pathologies may act synergistically with α-syn pathology to confer a worse prognosis. Understanding the relationships between these three distinct pathologies and their resultant clinical phenotypes are crucial to the development of effective disease-modifying treatments for PD and PDD.

High-speed atomic force microscopy reveals structural dynamics of amyloid β 1–42 aggregates

“…Alzheimer's disease | amyloidogenic proteins | kinetics | atomic force microscopy A myloid fibril accumulation is associated with numerous neurodegenerative diseases, including Alzheimer's (AD) (1-3), prionoses (4-7), Parkinson's (8)(9)(10)(11), and Huntington's (12). Nonhomologous genes encode the proteins involved in each disease, namely the amyloid β-protein (Aβ), prions (e.g., PrP, Sup35, Het-s), α-synuclein, and huntingtin, respectively.…”

Propagated but topologically distributed forebrain neurons expressing alpha-synuclein in aged macaques

“…It has recently been revealed that the α-syn pathology related to disease development is transmitted based on the neural linkage [18][19][20][21][22][23]. The present study defines that α-syn-positive neurons propagate topologically in accordance with the midbrain dopamine systems, as evidenced by the findings that α-syn-positive neurons appear in the striatum in an age-dependent fashion based on dopaminergic input loss along the nigrostriatal pathway responsible for PD.…”

Formation of neurodegenerative aggresome and death-inducing signaling complex in maternal diabetes-induced neural tube defects

“…Here, we show that misfolded proteins form aggregates and are resistant to degradation via the UPS and ALS. In addition, the protein aggregates contain α-Syn, Parkin, and Htt, which are also involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's diseases (19)(20)(21)(22). The presence of these aggregates in maternal diabetes-induced embryonic NTDs suggests that similar molecular processes may be occurring in diabetic embryopathy and neurodegenerative diseases.…”

“…These proteins are expressed in the neural epithelium during neurulation (28)(29)(30). Aggregation of these proteins may abolish their normal functions and also disturb intracellular signaling, as seen in neurodegenerative diseases (19)(20)(21)(22).…”

“…Aggregation of α-Synuclein (α-Syn), Parkin, and Huntingtin (Htt) has been found to be involved in the pathogenesis of Alzheimer's, Parkinson's, and Huntington's diseases (19)(20)(21)(22). Protein aggregates can be eliminated by the autophagic-lysosomal system (ALS) (23,24).…”