Neurodegeneration and Alzheimer's disease (AD). What Can Proteomics Tell Us About the Alzheimer's Brain?

Abstract

Neurodegenerative diseases, such as Alzheimers diseases (AD), are becoming more prevalent as the population ages. However, the mechanisms that lead to synapse destabilization and neuron death remain elusive. The advent of proteomics has allowed for high-throughput screening methods to search for biomarkers that could lead to early diagnosis and treatment and to identify alterations in the cellular proteome that could provide insight into disease etiology and possible treatment avenues. In this review, we have concentrated mainly on the findings that are related to how and whether proteomics studies have contributed to two aspects of AD research, the development of biomarkers for clinical diagnostics, and the recognition of proteins that can help elucidate the pathways leading to AD brain pathology. Neurodegenerative diseases are becoming more prevalent as the population ages, yet the mechanisms that lead to synapse destabilization and neuronal death remain elusive. The advent of proteomics has led to methods for highthroughput screening to search for biomarkers that can be used for the early diagnosis and treatment of various diseases and to identify alterations in the cellular proteome that can provide insight into disease etiology and potential avenues for treatment. How and why only specific classes of neurons are affected when a genetic mutation is identified in a ubiquitously expressed gene are major questions that underlie the study of neurodegeneration. Clear examples of this phenomenon are the mutations in amyloid precursor protein (APP) or presenilin 1 (PSEN1) and 2 (PSEN2) that occur in Alzheimer's disease (AD) 1 , which affect learning and memory circuits (1, 2); super oxide dismutase 1 (SOD1) mutations that specifically affect motor neurons (MNs) in amyotrophic lateral sclerosis (3); huntingtin mutations that affect cortico-striatal circuits in cases of Huntington's disease (4, 5) and Parkin and Pink1 mutations associated with autosomal recessive familial early-onset Parkinson disease targeting dopamine generating cells in the substantia nigra (6, 7).All the neurodegenerative diseases mentioned above are characterized by neuronal dysfunction and neuronal death. However, they are distinct in terms of their genetics, pathologies, phenotypes, and treatments. Proteomics studies have been performed to analyze differentially expressed proteins in different disease paradigms, however, the diversity of models and samples that have been included in these studies are too numerous to cover in a review. We have therefore focused mainly on studies performed in AD because it is the most prevalent neurodegenerative disorder (8) and a larger number of studies have been performed using similar biological samples. Thus, in this review, we have concentrated mainly on findings related to how and whether proteomics studies have contributed to the identification of biomarkers or to our understanding of brain pathology in AD.AD is a multifactorial and complex neurodegenerative disorder that is characterized by progressive ...

Neuroinflammation in Alzheimer’s disease: Pleiotropic roles for cytokines and neuronal pentraxins

“…Furthermore, due to the multifaceted etiopathology of AD, new proteomics research is needed to advance the understanding and diagnostic tools of this disease by looking at the molecular and neurophysiological mechanisms underlying AD [9,174–176]. Analysis of biochemical markers that can be used to diagnose the various stages of this disease, as well as elucidation of neurobiological changes that occur throughout AD, are vital to advancing this field.…”

“…Neurodegenerative processes that contribute to atrophy and memory decline occur in specific brain areas like the neocortex and limbic system and are characterized by synaptic damage and neuronal death, with these changes corresponding to the classical cognitive impairment and memory loss associated with AD [9,106–110]. In experiments looking at multiple sclerosis (MS), an inflammatory disease characterized by extensive demyelination, it has been found that neuroinflammation has detrimental effects on synaptic transmission, particularly in the hippocampus, further elucidating the hippocampal cognitive deficits and attenuation of synaptic plasticity that result in pathologies due to CNS inflammation [111,112].…”

“…This classification relies on a method that takes into account the age of the individual with the number of plaques and tangles that are present [4]. However, new proteomics research has suggested a different paradigm to better understand the multitude of factors that mechanistically contribute to the etiopathogenesis and progression of AD, which may complement or act downstream of amyloid and tau pathology [6–9]. …”

Conjugates of neuroprotective chaperone L-PGDS provide MRI contrast for detection of amyloid β-rich regions in live Alzheimer’s Disease mouse model brain

“…Supported by the correlation of AD symptoms with downregulation of L-PGDS concentration in the CSF of AD brain, we posit that L-PGDS targets Aβ in AD mouse brain with high turnover suggestive of fast kinetic binding [10][11][12]. Therefore, we reason that L-PGDS expressed in other brain regions takes part in other biological functions and can play a more active neuroprotective role.…”

Neuroproteomics: How Many Angels can be Identified in an Extract from the Head of a Pin?

“…In this case, a proteomics study of normal synaptic functions provides insights on new roles for neurodegeneration-associated proteins. Synapse dysfunction and loss are implicated in neurodegenerative diseases and the review of Moya-Alvarado et al (11) summarizes progress in applying proteomics to the pathophysiology and diagnosis of Alzheimer's disease. Links to neurological diseases are also seen in primary research papers in this issue.…”