Anti-amyloid: An antibody to cure Alzheimer’s or an attitude

Osborne, Olivia; Naranjo, Oandy; Heckmann, Bradlee L.; Dykxhoorn, Derek M.; Toborek, Michał

doi:10.1016/j.isci.2023.107461

Cited by 15 publications

(5 citation statements)

References 67 publications

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“…Given the above and the recent discussion about the validity of the amyloid hypothesis [139,140], it is possible that amyloid beta is not driving the wide-spread changes in cognitive function; that amyloid is only part of the pathology or that amyloid protein variants are critical; High-Fat Diet and EPA on Behavior and Physiology in APPswePS1dE9 Mice and/or that environmental or developmental interactions, study design and time course, age, and experimental methodology are relevant for understanding this disease. This is not a new realization, and previous literature suggests Alzheimer's is not amyloid-centric [141] and/or may have two partsa pre-amyloid stage and then a later amyloidassociated stage [142].…”

Section: Discussionmentioning

confidence: 97%

“…Recent calls for new drugs for AD have suggested targeting neuroinflammatory pathways and mitochondrial dysfunction [139]. Moreover, if, as recently proposed, AD is better characterized by dysfunction of metabolic parameters [144], then studies investigating diet, metabolic factors, behavior, glucocorticoids (a major metabolic hormone), and their associated pathways and impacts on neuronal function are needed.…”

Section: Discussionmentioning

confidence: 99%

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Impact of Long-Term Dietary High Fat and Eicosapentaenoic Acid on Behavior and Hypothalamic-Pituitary-Adrenal Axis Activity in Amyloidogenic APPswe/PSEN1dE9 Mice

Harris,

Yavari,

Ramalingam

et al. 2024

Neuroendocrinology

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Introduction: Alzheimer’s disease (AD) alters neurocognitive and emotional function and causes dysregulation of multiple homeostatic processes. The leading AD framework pins amyloid beta plaques and tau tangles as primary drivers of dysfunction. However, many additional variables, including diet, stress, sex, age, and pain tolerance, interact in ways that are not fully understood to impact the onset and progression of AD pathophysiology. We asked: (1) does high-fat diet, compared to low-fat diet, exacerbate AD pathophysiology and behavioral decline? And, (2) can supplementation with eicosapentaenoic (EPA)-enriched fish oil prevent high-fat-diet-induced changes? Methods: Male and female APPswePSdE9 mice, and their non-transgenic littermates, were randomly assigned to a diet condition (low-fat, high-fat, high-fat with EPA) and followed from 2 to 10 months of age. We assessed baseline corticosterone concentration during aging, pain tolerance, cognitive function, stress coping, and corticosterone response to a stressor. Results: Transgenic mice were consistently more active than non-transgenic mice but did not perform worse on either cognitive task, even though we recently reported that these same transgenic mice exhibited metabolic changes and had increased amyloid beta. Mice fed high-fat diet had higher baseline and post-stressor corticosterone, but diet did not impact cognition or pain tolerance. Sex had the biggest influence, as female mice were consistently more active and had higher corticosterone than males. Conclusion: Overall, diet, genotype, and sex did not have consistent impacts on outcomes. We found little support for predicted interactions and correlations, suggesting diet impacts metabolic function and amyloid beta levels, but these outcomes do not translate to changes in behaviors measured here.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Impact of Long-Term Dietary High Fat and Eicosapentaenoic Acid on Behavior and Hypothalamic-Pituitary-Adrenal Axis Activity in Amyloidogenic APPswe/PSEN1dE9 Mice

Harris,

Yavari,

Ramalingam

et al. 2024

Neuroendocrinology

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“…concentrations of substrates (2,5,10,25, and 50 μM for BTCI). To obtain estimates of the inhibition type, reciprocal plots of 1/V versus 1/[S] were constructed by using the reported method with minor modifications.…”

Section: Kinetic Analysis Of Hbuche Inhibitionmentioning

confidence: 99%

“…Overcleavage of amyloid precursor protein leads to the accumulation of abnormal Aβ, which results in synaptic and neuronal loss, ultimately leading to the atrophy of patients' brain. [ 10 ] Therefore, selective inhibitor of BuChE with function for preventing the accumulation of Aβ is a potential strategy for treating AD.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and activity evaluation of novel multitargeted l‐tryptophan derivatives with powerful antioxidant activity against Alzheimer's disease

Zeng,

Cheng,

et al. 2024

Archiv der Pharmazie

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Alzheimer's disease (AD) is a multifactorial neurological disease, and the multitarget directed ligand (MTDL) strategy may be an effective approach to delay its progression. Based on this strategy, 27 derivatives of l‐tryptophan, 3a‐1–3d‐1, were designed, synthesized, and evaluated for their biological activity. Among them, IC50 (inhibitor concentration resulting in 50% inhibitory activity) values of compounds 3a‐18 and 3b‐1 were 0.58 and 0.44 μM for human serum butyrylcholinesterase (hBuChE), respectively, and both of them exhibited more than 30‐fold selectivity for human serum acetylcholinesterase. Enzyme kinetics studies showed that these two compounds were mixed inhibitors of hBuChE. In addition, these two derivatives possessed extraordinary antioxidant activity in OH radical scavenging and oxygen radical absorption capacity fluorescein assays. Meanwhile, these compounds could also prevent β‐amyloid (Aβ) self‐aggregation and possessed low toxicity on PC12 and AML12 cells. Molecular modeling studies revealed that these two compounds could interact with the choline binding site, acetyl binding site, and peripheral anionic site to exert submicromolar BuChE inhibitory activity. In the vitro blood–brain barrier permeation assay, compounds 3a‐18 and 3b‐1 showed enough blood–brain barrier permeability. In drug‐likeness prediction, compounds 3a‐18 and 3b‐1 showed good gastrointestinal absorption and a low risk of human ether‐a‐go‐go‐related gene toxicity. Therefore, compounds 3a‐18 and 3b‐1 are potential multitarget anti‐AD lead compounds, which could work as powerful antioxidants with submicromolar selective inhibitory activity for hBuChE as well as prevent Aβ self‐aggregation.

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“…AD neuropathogenesis involves the accumulation of amyloid-beta (Aβ) plaques, neurofibrillary tangles (NFTs) (Wood et al, 1986), neuroinflammation (Calsolaro and Edison, 2016), glial cell dysfunction (De Sousa, 2022), lipid droplet (LD) accumulation (Marschallinger et al, 2020), aberrant lipid and lipoprotein processing (Cleland et al, 2021;Kao et al, 2020), and brain glucose hypometabolism (Abeysinghe et al, 2020;Johri, 2021;Mullins et al, 2018) leading to neurodegeneration (Masters et al, 1985;Serrano-Pozo et al, 2011;Wood et al, 1986) and cognitive decline (Porsteinsson et al, 2021). Despite the complexity of AD, current FDA-approved therapies only target one, if any, of the underlying facets of the disease and may not be available to, or effective, in many subjects with AD (Liu and Howard, 2021;Manly and Glymour, 2021;Osborne et al, 2023;Ramanan and Day, 2023;van Dyck et al, 2023). Hence, there is a clear need to identify alternative strategies that can simultaneously target many of the underlying mechanisms contributing to AD pathology and may improve outcomes for those living with or at risk of developing AD.…”

Section: Introductionmentioning

confidence: 99%

Altered Metabolism and DAM-signatures in Female Brains and Microglia with Aging

Cleland,

Potter,

Buck

et al. 2023

Preprint

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Despite Alzheimer’s disease (AD) disproportionately affecting women, the mechanisms remain elusive. In AD, microglia undergo ‘metabolic reprogramming’, which contributes to microglial dysfunction and AD pathology. However, how sex and age contribute to metabolic reprogramming in microglia is understudied. Here, we use metabolic imaging, transcriptomics, and metabolic assays to probe age-and sex-associated changes in brain and microglial metabolism. Glycolytic and oxidative metabolism in the whole brain was determined using Fluorescence Lifetime Imaging Microscopy (FLIM). Young female brains appeared less glycolytic than male brains, but with aging, the female brain became ‘male-like.’ Transcriptomic analysis revealed increased expression of disease-associated microglia (DAM) genes (e.g.,ApoE,Trem2,LPL), and genes involved in glycolysis and oxidative metabolism in microglia from aged females compared to males. To determine whether estrogen can alter the expression of these genes, BV-2 microglia-like cell lines, which abundantly express DAM genes, were supplemented with 17β-estradiol (E2). E2 supplementation resulted in reduced expression of DAM genes, reduced lipid and cholesterol transport, and substrate-dependent changes in glycolysis and oxidative metabolism. Consistent with the notion that E2 may suppress DAM-associated factors, LPL activity was elevated in the brains of aged female mice. Similarly, DAM gene and protein expression was higher in monocyte-derived microglia-like (MDMi) cells derived from middle-aged females compared to age-matched males and was responsive to E2 supplementation. FLIM analysis of MDMi from young and middle-aged females revealed reduced oxidative metabolism and FAD+ with age. Overall, our findings show that altered metabolism defines age-associated changes in female microglia and suggest that estrogen may inhibit the expression and activity of DAM-associated factors, which may contribute to increased AD risk, especially in post-menopausal women.

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Anti-amyloid: An antibody to cure Alzheimer’s or an attitude

Cited by 15 publications

References 67 publications

Impact of Long-Term Dietary High Fat and Eicosapentaenoic Acid on Behavior and Hypothalamic-Pituitary-Adrenal Axis Activity in Amyloidogenic APPswe/PSEN1dE9 Mice

Impact of Long-Term Dietary High Fat and Eicosapentaenoic Acid on Behavior and Hypothalamic-Pituitary-Adrenal Axis Activity in Amyloidogenic APPswe/PSEN1dE9 Mice

Design, synthesis, and activity evaluation of novel multitargeted l‐tryptophan derivatives with powerful antioxidant activity against Alzheimer's disease

Altered Metabolism and DAM-signatures in Female Brains and Microglia with Aging

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