Differential protein expression in diverse brain areas of Parkinson\u2019s and Alzheimer\u2019s disease patients

A R Esteves,S M Cardoso

doi:10.1038/s41598-020-70174-z

Abstract

Many hypotheses have been postulated to define the etiology of sporadic Parkinson’s and Alzheimer’s disorders (PD and AD) but there is no consensus on what causes these devastating age-related diseases. Braak staging of both pathologies helped researchers to better understand the progression and to identify their prodromal and symptomatic phases. Indeed, it is well accepted that Lewy body pathology and neurofibrillary tangles appearance correlates with disease progression and severity of symptoms in PD and AD, respectively. Additionally, several studies in PD and AD models try to disclose which cellular mechanisms are defaulted and trigger the neurodegenerative process that culminates with neuronal death causing PD and AD classical symptomatology. Herein, we determined expression levels of proteins involved in microtubule assembly, autophagic-lysosomal pathway and unfolded protein response in the cortex, hippocampus and SNpc of PD and AD patients, vascular dementia patients and aged-match controls. The differential expression allowed us to determine which pathways are determinant to synaptic dysfunction and to establish a time line for disease progression. Our results allow us to challenge the hypothesis that both PD and AD pathologies are caused by α-synuclein or Aβ pathology propagation throughout the brain in a prion-like manner.

Highlights

Many hypotheses have been postulated to define the etiology of sporadic Parkinson’s and Alzheimer’s disorders (PD and AD) but there is no consensus on what causes these devastating age-related diseases
In post-mortem human brain samples obtained from Parkinson’s diseases (PD) patients, Braak stage IV–VI, we observe a decrease in acetylated-tubulin and in acetylated-tau levels in substantia nigra pars compacta (SNpc) (Fig. 1)
Our group previous work showed, in different PD models, that mitochondrial deficits lead to deficient intracellular traffic which results in incomplete autophagosome degradation and reduced autophagosome and mitochondrial movements culminating in a poor SNCA aggregate clearance[18,25,26]

Summary

Introduction

Many hypotheses have been postulated to define the etiology of sporadic Parkinson’s and Alzheimer’s disorders (PD and AD) but there is no consensus on what causes these devastating age-related diseases Braak staging of both pathologies helped researchers to better understand the progression and to identify their prodromal and symptomatic phases. AD is associated with neuronal loss, progressive synaptic and mitochondrial dysfunction, accompanied by the deposition of Aβ peptides and abnormal tau protein[7] These hallmarks have been used as diagnostic criteria for the d isease[2], but whether they are causes of AD or merely consequences is yet unknown. Vascular dementia (VD) is considered the second most common cause of cognitive impairment in the elderly population after AD with memory and cognitive function impairment as a consequence of reduced blood flow to the b rain[11] The heterogeneity of this disease makes it challenging to elucidate the underlying mechanisms and neuropathology. Regarding VD pathophysiology, abnormal energy metabolism together with oxidative stress and reactive nitrogen species generation are known to contribute to cognitive impairments in VD culminating in hemodynamic abnormalities and neurovascular d amage[13]

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Results

Conclusion