Low soluble amyloid-β 42 is associated with smaller brain volume in Parkinson's disease

Espay, Alberto J.; Lafontant, David-Erick; Poston, Kathleen L.; Caspell‐Garcia, Chelsea; Marsili, Luca; Cho, Hyunkeun Ryan; McDaniel, Colin; Kim, Nessa; Coffey, Christopher S.; Mahajan, Abhimanyu; Ezzat, Kariem; Sturchio, Andrea

doi:10.1016/j.parkreldis.2021.10.010

Cited by 10 publications

(4 citation statements)

References 28 publications

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“…Using the same dataset (ADNI), they directly tested the hypothesis that higher CSF-Aβ42 levels correspond to better cognitive status of patients, even after excluding the effect of the density of deposits. To interpret this, it was hypothesized that soluble Aβ42 has some important biological function, so low levels of soluble Aβ42 cause AD [23,[27][28][29]. Unfortunately, this interpretation has difficulty explaining why the levels of soluble Aβ42 in healthy patients with high density of deposits are the same as the levels of soluble Aβ42 in patients with AD with low density of deposits -the fact which can be found in the figures and was confirmed by us during statistical analysis of ADNI dataset.…”

Section: Amyloid Biomarkers Of Ad: Two Biomarkers -Two Paradoxesmentioning

confidence: 78%

Amyloid Degradation Toxicity Hypothesis: Integrative Theory of Alzheimer’s Disease

Zaretsky,

Zaretskaia

2023

Preprint

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The manuscript presents the comprehensive integrative theory of the etiology and pathogenesis of Alzheimer’s disease - the amyloid degradation toxicity hypothesis - and describes the logic that underlies it.The analysis of amyloid biomarkers and stable-isotope label kinetics (SILK) studies suggest that AD diagnosis is associated with higher cellular uptake of beta-amyloid. Uptake of beta-amyloid by cells is needed for its cytotoxicity, so the uptake rate should correlate with the rate of neurodegeneration. Also, the initial step in forming extracellular aggregates cannot occur in the interstitial fluid due to the extremely low concentration of beta-amyloid but can occur intralysosomally. Therefore, the density of extracellular aggregates should positively correlate with the rate of cellular amyloid uptake. The model, which considers that both cytotoxicity and aggregation of beta-amyloid are defined by cellular uptake, successfully reproduces the probability distribution of AD diagnosis in the population. Cellular uptake of beta-amyloid is mediated by endocytosis. Endocytosed beta-amyloid induces lysosomal permeabilization that occurs without plasma membrane damage. Lysosomal permeabilization explains ion disturbances, such as an accumulation of intracellular calcium, caused by cell exposure to extracellular beta-amyloid. Some amyloid fragments, produced from beta-amyloid by lysosomal proteases, can form membrane channels in lysosomal membranes, which are large enough to leak cathepsins to the cytoplasm. Appearance of proteases in the cytoplasm results in necrosis and/or initiation of apoptosis. If the cell survives, the damage of lysosomes leads to autophagy failure and slow recycling of mitochondria, promoting the production of reactive oxygen species and potentiating cell damage.Considering the above, the integrative theory of AD etiology and pathogenesis can be formulated. The etiology of AD is the membrane channel formation by amyloid fragments produced in lysosomes. The pathogenesis includes lysosomal permeabilization by giant membrane channels, which leak lysosomal proteases into the cytoplasm. The correlation between the density of amyloid aggregates and the probability of AD appears because the intensity of cellular uptake defines both aggregation rates in vivo and cytotoxicity of beta-amyloid.The amyloid degradation toxicity hypothesis is the integrative theory of Alzheimer’s disease (AD). It successfully interprets multiple phenomena and paradoxes associated with AD pathobiology at various levels, from molecular and cellular to biomarkers. The hypothesis explains the limitations of currently used biomarkers of AD and proposes etiology-related parameters. These parameters could be measured in humans and become novel diagnostic and prognostic clinical tools. Based on the proposed framework, we foresee the development of effective medications to treat, stall the progression of, or prevent disease development.

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Section: Amyloid Biomarkers Of Ad: Two Biomarkers -Two Paradoxesmentioning

confidence: 78%

Amyloid Degradation Toxicity Hypothesis: Integrative Theory of Alzheimer’s Disease

Zaretsky,

Zaretskaia

2023

Preprint

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“…It is apparent that there is a quantitative loss of active, functional, soluble, unstable α-Syn protein because of its transition into insoluble, inactive, highly stable cross-β inclusions, and consequently, a loss of physiological functions of α-Syn, which are critical for neuronal survival. Such depleted α-Syn levels have been associated with smaller brain volume and neurotoxicity in PD, where higher levels of α-Syn are required for the preservation of the brain volume [97]. On the other hand, overexpression of α-Syn levels (toxic dose effect) has been associated with more malignant phenotypes [98] because of its propensity to aggregate through nucleation and the consequent reduction of the normal protein levels.…”

Section: Evidence Of Phenotypic Switching and Structure-toxicity Rela...mentioning

confidence: 99%

Nonintuitive Immunogenicity and Plasticity of Alpha-Synuclein Conformers: A Paradigm for Smart Delivery of Neuro-Immunotherapeutics

Abioye,

Akintade,

Mitchell

et al. 2024

Pharmaceutics

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: Despite the extensive research successes and continuous developments in modern medicine in terms of diagnosis, prevention, and treatment, the lack of clinically useful disease-modifying drugs or immunotherapeutic agents that can successfully treat or prevent neurodegenerative diseases is an ongoing challenge. To date, only one of the 244 drugs in clinical trials for the treatment of neurodegenerative diseases has been approved in the past decade, indicating a failure rate of 99.6%. In corollary, the approved monoclonal antibody did not demonstrate significant cognitive benefits. Thus, the prevalence of neurodegenerative diseases is increasing rapidly. Therefore, there is an urgent need for creative approaches to identifying and testing biomarkers for better diagnosis, prevention, and disease-modifying strategies for the treatment of neurodegenerative diseases. Overexpression of the endogenous α-synuclein has been identified as the driving force for the formation of the pathogenic α-synuclein (α-Syn) conformers, resulting in neuroinflammation, hypersensitivity, endogenous homeostatic responses, oxidative dysfunction, and degeneration of dopaminergic neurons in Parkinson’s disease (PD). However, the conformational plasticity of α-Syn proffers that a certain level of α-Syn is essential for the survival of neurons. Thus, it exerts both neuroprotective and neurotoxic (regulatory) functions on neighboring neuronal cells. Furthermore, the aberrant metastable α-Syn conformers may be subtle and difficult to detect but may trigger cellular and molecular events including immune responses. It is well documented in literature that the misfolded α-Syn and its conformers that are released into the extracellular space from damaged or dead neurons trigger the innate and adaptive immune responses in PD. Thus, in this review, we discuss the nonintuitive plasticity and immunogenicity of the α-Syn conformers in the brain immune cells and their physiological and pathological consequences on the neuroimmune responses including neuroinflammation, homeostatic remodeling, and cell-specific interactions that promote neuroprotection in PD. We also critically reviewed the novel strategies for immunotherapeutic delivery interventions in PD pathogenesis including immunotherapeutic targets and potential nanoparticle-based smart drug delivery systems. It is envisioned that a greater understanding of the nonintuitive immunogenicity of aberrant α-Syn conformers in the brain’s microenvironment would provide a platform for identifying valid therapeutic targets and developing smart brain delivery systems for clinically effective disease-modifying immunotherapeutics that can aid in the prevention and treatment of PD in the future.

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“…7 High SNCA expression (REP1 genotypes) is "paradoxically" associated with better motor and cognitive outcomes, 8 and high, not low, α-synuclein levels are associated with preservation of brain volume in PD. 9 Physically, proteins do not replicate; they precipitate. This irreversible process of nucleation follows the second law of thermodynamics and Gibbs free energy equation.…”

Section: A New Paradigm: Proteinopeniamentioning

confidence: 99%

“…Even in those with genetically overexpressed α-synuclein, such as SNCA duplication, the levels of soluble α-synuclein are low, not high . High SNCA expression (REP1 genotypes) is “paradoxically” associated with better motor and cognitive outcomes, and high, not low, α-synuclein levels are associated with preservation of brain volume in PD …”

Section: A New Paradigm: Proteinopeniamentioning

confidence: 99%

Abandoning the Proteinopathy Paradigm in Parkinson Disease

Espay

Okun

2023

JAMA Neurol

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Low soluble amyloid-β 42 is associated with smaller brain volume in Parkinson's disease

Cited by 10 publications

References 28 publications

Amyloid Degradation Toxicity Hypothesis: Integrative Theory of Alzheimer’s Disease

Amyloid Degradation Toxicity Hypothesis: Integrative Theory of Alzheimer’s Disease

Nonintuitive Immunogenicity and Plasticity of Alpha-Synuclein Conformers: A Paradigm for Smart Delivery of Neuro-Immunotherapeutics

Abandoning the Proteinopathy Paradigm in Parkinson Disease

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