Using Proteomics to Understand Alzheimer’s Disease Pathogenesis

Drummond, Eleanor; Wısnıewskı, Thomas

doi:10.15586/alzheimersdisease.2019.ch3

Cited by 16 publications

(11 citation statements)

References 83 publications

(101 reference statements)

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“…Mass spectrometry-based proteomics analysis of laser dissected tissue or cells has become a useful technology to identify proteins specifically in pathological conditions [ 7 , 16 , 20 ]. In this study we applied a single-cell resolution proteomics approach that provides for the first time an overview of changes in the proteome of neurons containing GVD and in those containing neurofibrillary tangles.…”

Section: Discussionmentioning

confidence: 99%

The proteome of granulovacuolar degeneration and neurofibrillary tangles in Alzheimer’s disease

et al. 2021

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Granulovacuolar degeneration (GVD) is a common feature in Alzheimer’s disease (AD). The occurrence of GVD is closely associated with that of neurofibrillary tangles (NFTs) and GVD is even considered to be a pre-NFT stage in the disease process of AD. Currently, the composition of GVD bodies, the mechanisms associated with GVD and how GVD exactly relates to NFTs is not well understood. By combining immunohistochemistry (IHC) and laser microdissection (LMD) we isolated neurons with GVD and those bearing tangles separately from human post-mortem AD hippocampus (n = 12) using their typical markers casein kinase (CK)1δ and phosphorylated tau (AT8). Control neurons were isolated from cognitively healthy cases (n = 12). 3000 neurons per sample were used for proteome analysis by label free LC–MS/MS. In total 2596 proteins were quantified across samples and a significant change in abundance of 115 proteins in GVD and 197 in tangle bearing neurons was observed compared to control neurons. With IHC the presence of PPIA, TOMM34, HSP70, CHMP1A, TPPP and VXN was confirmed in GVD containing neurons. We found multiple proteins localizing specifically to the GVD bodies, with VXN and TOMM34 being the most prominent new protein markers for GVD bodies. In general, protein groups related to protein folding, proteasomal function, the endolysosomal pathway, microtubule and cytoskeletal related function, RNA processing and glycolysis were found to be changed in GVD neurons. In addition to these protein groups, tangle bearing neurons show a decrease in ribosomal proteins, as well as in various proteins related to protein folding. This study, for the first time, provides a comprehensive human based quantitative assessment of protein abundances in GVD and tangle bearing neurons. In line with previous functional data showing that tau pathology induces GVD, our data support the model that GVD is part of a pre-NFT stage representing a phase in which proteostasis and cellular homeostasis is disrupted. Elucidating the molecular mechanisms and cellular processes affected in GVD and its relation to the presence of tau pathology is highly relevant for the identification of new drug targets for therapy.

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Section: Discussionmentioning

confidence: 99%

The proteome of granulovacuolar degeneration and neurofibrillary tangles in Alzheimer’s disease

et al. 2021

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“…More recently, proteomics has emerged as a method that allows for high throughput analysis of protein expression in small tissue samples [ 56 ], including post-mortem brain tissue from AD patients [ 57 , 58 ], and which has allowed for the study of changes in the interaction between presynaptic proteins [ 59 ], including SNAP25 and syntaxin [ 60 ]. Increased SNAP25 and syntaxin interaction results in reduced glutamatergic synaptic transmission [ 61 , 62 ] and decreased interaction between these proteins has been observed in the brains of AD patients, along with decreased levels of Complexin II [ 63 ], effects which would be expected to result in increased excitatory synaptic transmission [ 64 , 65 ].…”

Section: Ca 2+ Dysregulation and Synaptic Defecmentioning

confidence: 99%

Ca2+ Dyshomeostasis Disrupts Neuronal and Synaptic Function in Alzheimer’s Disease

McDaid

Mustaly-Kalimi

Stutzmann

2020

Cells

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Ca2+ homeostasis is essential for multiple neuronal functions and thus, Ca2+ dyshomeostasis can lead to widespread impairment of cellular and synaptic signaling, subsequently contributing to dementia and Alzheimer’s disease (AD). While numerous studies implicate Ca2+ mishandling in AD, the cellular basis for loss of cognitive function remains under investigation. The process of synaptic degradation and degeneration in AD is slow, and constitutes a series of maladaptive processes each contributing to a further destabilization of the Ca2+ homeostatic machinery. Ca2+ homeostasis involves precise maintenance of cytosolic Ca2+ levels, despite extracellular influx via multiple synaptic Ca2+ channels, and intracellular release via organelles such as the endoplasmic reticulum (ER) via ryanodine receptor (RyRs) and IP3R, lysosomes via transient receptor potential mucolipin channel (TRPML) and two pore channel (TPC), and mitochondria via the permeability transition pore (PTP). Furthermore, functioning of these organelles relies upon regulated inter-organelle Ca2+ handling, with aberrant signaling resulting in synaptic dysfunction, protein mishandling, oxidative stress and defective bioenergetics, among other consequences consistent with AD. With few effective treatments currently available to mitigate AD, the past few years have seen a significant increase in the study of synaptic and cellular mechanisms as drivers of AD, including Ca2+ dyshomeostasis. Here, we detail some key findings and discuss implications for future AD treatments.

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“…The next step is to extrapolate these data to body fluids (CSF and blood). The most promising technique would be ultra‐deep serum discovery by TMT‐LC/LC‐MS/MS, and a validation experiment by TOMAHAQ targeted LC‐MS3 158‐161 . Blood biomarkers should be the focus in the future as it is a minimally invasive technique and routinely done procedure.…”

Section: Future Perspectivesmentioning

confidence: 99%

“…and a validation experiment by TOMAHAQ targeted LC-MS3. [158][159][160][161] Blood biomarkers should be the focus in the future as it is a minimally invasive technique and routinely done procedure.…”

Section: Diagnosis and Prognosismentioning

confidence: 99%

Precision health in Alzheimer disease: Risk assessment‐based strategies

Azar

Salama

Chidambaram

et al. 2021

Precision Medical Sciences

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Alzheimer disease (AD) is a chronic neurodegenerative condition that affects an individual's cognitive function over an extended period. Treatment and prevention for AD have long been sought after; however, no strategy has yet been successful, as individuals with cognitive impairment usually present to the clinic when they have reached an advanced stage of the disease. The disease is progressive and multifactorial in its pathogenesis. Precision medicine (PM) is the new era of medicine comprising a holistic approach in dealing with diseases. With scientific innovations, PM has improved our disease knowledge, altered diagnoses and therapy approaches resulting in a more precise, predictive, preventative and personalized patient care. PM in AD focuses, among other things, on stratifying individuals according to their risk factors of developing the disease and applying preventative strategies and personalized treatment approaches for a better outcome. In this mini‐review, we have focused on a few modifiable and non‐modifiable risk factors and presented recommendations for future consideration to implement.

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Using Proteomics to Understand Alzheimer’s Disease Pathogenesis

Cited by 16 publications

References 83 publications

The proteome of granulovacuolar degeneration and neurofibrillary tangles in Alzheimer’s disease

The proteome of granulovacuolar degeneration and neurofibrillary tangles in Alzheimer’s disease

Ca2+ Dyshomeostasis Disrupts Neuronal and Synaptic Function in Alzheimer’s Disease

Precision health in Alzheimer disease: Risk assessment‐based strategies

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