High Soluble Amyloid-β42 Predicts Normal Cognition in Amyloid-Positive Individuals with Alzheimer’s Disease-Causing Mutations

Sturchio, Andrea; Dwivedi, Alok; Malm, Tarja; Wood, Matthew J.; Cilia, Roberto; Sharma, Jennifer; Hill, Emily J.; Schneider, Lon S.; Graff‐Radford, Neill R.; Mori, Hiroshi; Nübling, Georg; Andaloussi, Samir El; Svenningsson, Per; Ezzat, Kariem; Espay, Alberto J.

doi:10.3233/jad-220808

Cited by 34 publications

(19 citation statements)

References 38 publications

(54 reference statements)

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“…This complex interplay between CaM, CaMBPs and Aβ-receptors may explain why no successful therapy has been developed to treat the various forms of AD. For example, attempts to treat AD by inhibiting BACE1 have not only been unsuccessful, but they have also led to confusing and, sometimes, contradictory results [ 1 , 52 ]. This could be explained both by the multiple normal physiological functions of Aβ in cells and/or by the multifaceted interplay between this CaM-binding peptide, its CaMBP/Aβ-receptors and the concomitant regulatory role of CaM and other CaMBPs, such as CaMKII and PP2B, on those receptors.…”

Section: Discussionmentioning

confidence: 99%

Calmodulin and Amyloid Beta as Coregulators of Critical Events during the Onset and Progression of Alzheimer’s Disease

O’Day

2023

IJMS

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Calmodulin (CaM) and a diversity of CaM-binding proteins (CaMBPs) are involved in the onset and progression of Alzheimer’s disease (AD). In the amyloidogenic pathway, AβPP1, BACE1 and PSEN-1 are all calcium-dependent CaMBPs as are the risk factor proteins BIN1 and TREM2. Ca2+/CaM-dependent protein kinase II (CaMKII) and calcineurin (CaN) are classic CaMBPs involved in memory and plasticity, two events impacted by AD. Coupled with these events is the production of amyloid beta monomers (Aβ) and oligomers (Aβo). The recent revelations that Aβ and Aβo each bind to both CaM and to a host of Aβ receptors that are also CaMBPs adds a new level of complexity to our understanding of the onset and progression of AD. Multiple Aβ receptors that are proven CaMBPs (e.g., NMDAR, PMCA) are involved in calcium homeostasis an early event in AD and other neurodegenerative diseases. Other CaMBPs that are Aβ receptors are AD risk factors while still others are involved in the amyloidogenic pathway. Aβ binding to receptors not only serves to control CaM’s ability to regulate critical proteins, but it is also implicated in Aβ turnover. The complexity of the Aβ/CaM/CaMBP interactions is analyzed using two events: Aβ generation and NMDAR function. The interactions between Aβ, CaM and CaMBPs reveals a new level of complexity to critical events associated with the onset and progression of AD and may help to explain the failure to develop successful therapeutic treatments for the disease.

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Section: Discussionmentioning

confidence: 99%

Calmodulin and Amyloid Beta as Coregulators of Critical Events during the Onset and Progression of Alzheimer’s Disease

O’Day

2023

IJMS

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“…Yet, it is also possible that these individuals were gifted with pragmatic adaptability that allowed them to compensate for the cognitive decline corresponding to cerebral neuropathology. Finally, it is possible that AD-resilient individuals had higher cerebrospinal fluid levels of fibrillogenic soluble 42-amino acid amyloid-beta-peptide (Aβ 42 ) leading to lower levels in the brain, which have been shown to be associated with normal cognition, even in the presence of insoluble cerebral amyloid plaques [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Characteristics and Predictors of Alzheimer’s Disease Resilience Phenotype

Sin

Cheng

Roseman

et al. 2023

JCM

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Alzheimer’s disease (AD) is characterized by cognitive impairment in the presence of cerebral amyloid plaques and neurofibrillary tangles. Less is known about the characteristics and predictors of resilience to cognitive impairment in the presence of neuropathological evidence of AD, the focus of this study. Of 3170 adults age ≥65 years in the National Alzheimer’s Coordinating Center (NACC) brain autopsy cohort, 1373 had evidence of CERAD level moderate to frequent neuritic plaque density and Braak stage V–VI neurofibrillary tangles. Resilience was defined by CDR-SOB and CDR-Global scores of 0–2.5 and 0–0.5, respectively, and non-resilience, CDR-SOB and CDR-Global scores >2.5 and >0.5, respectively. Multivariable logistic regression models were used to examine the independent associations of patient characteristics with resilience. There were 62 participants (4.8%) with resilience. Those with resilience were older (mean age, 88.3 vs. 82.4 years), more likely to be women (61.3% vs. 47.3%) and had a lower prevalence of the APOE-e4 carrier (41.9% vs. 56.2%). They also had a higher prevalence of hypertension, heart failure, atrial fibrillation, diuretic use, beta-blocker use, and APOE-e2 carrier status. Greater age at death, diuretic use, and APOE-e2 were the only characteristics independently associated with higher odds of the AD resilience phenotype (adjusted OR, 1.09; 95% CI, 1.05–1.13; p < 0.01; 2.00 (1.04–3.87), p = 0.04, 2.71 (1.31–5.64), p < 0.01, respectively). The phenotype of resilience to cognitive impairment is uncommon in older adults who have neuropathological evidence of AD.

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“…Method III enables isolation of highly pure Aβ dimers and monomers from amyloid plaques. While we have shown dimers to have disease relevant activity (Shankar et al, 2008;Brinkmalm et al, 2019;Zott et al, 2019), certain reports indicate that Aβ monomer has beneficial effects (Plant et al, 2006;Puzzo et al, 2008;Sturchio et al, 2022;Zhou et al, 2022). Utilization of Method III should allow a direct comparison of the activities of monomers and dimers, and the design of agents that would inhibit the adverse effects of dimers without impairing the potentially beneficial effects of monomers.…”

Section: Discussionmentioning

confidence: 90%

Methods for the isolation and analysis of Aβ from postmortem brain

Hong

DeSousa

et al. 2023

Front. Neurosci.

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Amyloid β-protein (Aβ) plays an initiating role in Alzheimer’s disease (AD), but only a small number of groups have studied Aβ extracted from human brain. Most prior studies have utilized synthetic Aβ peptides, but the relevance of these test tube experiments to the conditions that prevail in AD is uncertain. Here, we describe three distinct methods for studying Aβ from cortical tissue. Each method allows the analysis of different ranges of species thus enabling the examination of different questions. The first method allows the study of readily diffusible Aβ with a relatively high specific activity. The second enables the analysis of readily solubilized forms of Aβ the majority of which are inactive. The third details the isolation of true Aβ dimers which have disease-related activity. We also describe a bioassay to study the effects of Aβ on the neuritic integrity of iPSC-derived human neurons. The combined use of this bioassay and the described extraction procedures provides a platform to investigate the activity of different forms and mixtures of Aβ species, and offers a tractable system to identify strategies to mitigate Aβ mediated neurotoxicity.

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High Soluble Amyloid-β42 Predicts Normal Cognition in Amyloid-Positive Individuals with Alzheimer’s Disease-Causing Mutations

Cited by 34 publications

References 38 publications

Calmodulin and Amyloid Beta as Coregulators of Critical Events during the Onset and Progression of Alzheimer’s Disease

Calmodulin and Amyloid Beta as Coregulators of Critical Events during the Onset and Progression of Alzheimer’s Disease

Characteristics and Predictors of Alzheimer’s Disease Resilience Phenotype

Methods for the isolation and analysis of Aβ from postmortem brain

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