Amyloid Precursor Protein: A Regulatory Hub in Alzheimer's Disease

doi:10.14336/ad.2023.0308

Cited by 6 publications

(6 citation statements)

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“…DNPZ is known to inhibit the activity of BuChE and ADA, reduce LP and increase NO levels, and enhance antioxidant status. It also regulates the endocytic trafficking of APP by upregulating the expression of sorting nexin protein-33 (SNX33) [ 49 , 50 ]. The present study showed that the two lead compounds, and in particular 3c , have AChE inhibitory and antioxidant activity comparable to the reference drug DNPZ in the mouse SC model.…”

Section: Discussionmentioning

confidence: 99%

Tailored Melatonin- and Donepezil-Based Hybrids Targeting Pathognomonic Changes in Alzheimer’s Disease: An In Vitro and In Vivo Investigation

Mihaylova,

Angelova,

Tchekalarova

et al. 2024

IJMS

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A plethora of pathophysiological events have been shown to play a synergistic role in neurodegeneration, revealing multiple potential targets for the pharmacological modulation of Alzheimer’s disease (AD). In continuation to our previous work on new indole- and/or donepezil-based hybrids as neuroprotective agents, the present study reports on the beneficial effects of lead compounds of the series on key pathognomonic features of AD in both cellular and in vivo models. An enzyme-linked immunosorbent assay (ELISA) was used to evaluate the anti-fibrillogenic properties of 15 selected derivatives and identify quantitative changes in the formation of neurotoxic β-amyloid (Aβ42) species in human neuronal cells in response to treatment. Among the most promising compounds were 3a and 3c, which have recently shown excellent antioxidant and anticholinesterase activities, and, therefore, have been subjected to further in vivo investigation in mice. An acute toxicity study was performed after intraperitoneal (i.p.) administration of both compounds, and 1/10 of the LD50 (35 mg/kg) was selected for subacute treatment (14 days) with scopolamine in mice. Donepezil (DNPZ) and/or galantamine (GAL) were used as reference drugs, aiming to establish any pharmacological superiority of the multifaceted approach in battling hallmark features of neurodegeneration. Our promising results give first insights into emerging disease-modifying strategies to combine multiple synergistic activities in a single molecule.

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Section: Discussionmentioning

confidence: 99%

Tailored Melatonin- and Donepezil-Based Hybrids Targeting Pathognomonic Changes in Alzheimer’s Disease: An In Vitro and In Vivo Investigation

Mihaylova,

Angelova,

Tchekalarova

et al. 2024

IJMS

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“…Two examples include APP and PIAS1. The protein encoded by APP is essential to the pathophysiology of Alzheimer’s Disease [ 58 ]. There are also data indicating that this protein, or fragments of it, have anti-viral properties against IAV as well as other viruses [ 59 , 60 ].…”

Section: Discussionmentioning

confidence: 99%

Influenza virus infection exacerbates gene expression related to neurocognitive dysfunction in brains of old mice

Wu,

Alexander,

Booth

et al. 2024

Immun Ageing

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Background Age > 65 years is a key risk factor for poor outcomes after human influenza infection. Specifically, in addition to respiratory disease, non-neurotropic influenza A virus (IAV) causes neuro-cognitive complications, e.g. new onset depression and increases the risk of dementia after hospitalization. This study aimed to identify potential mechanisms of these effects by determining differences between young and old mice in brain gene expression in a mouse model of non-neurotropic IAV infection. Methods Young (12 weeks) and old (70 weeks) C57Bl/6J mice were inoculated intranasally with 200 PFU H1N1 A/PR/34/8 (PR8) or sterile PBS (mock). Gene expression in lung and brain was measured by qRT-PCR and normalized to β-actin. Findings were confirmed using the nCounter Mouse Neuroinflammation Array (NanoString) and analyzed with nSolver 4.0 and Ingenuity Pathway Analysis (IPA, Qiagen). Results IAV PR8 did not invade the central nervous system. Young and old mice differed significantly in brain gene expression at baseline and during non-neurotropic IAV infection. Expression of brain Ifnl, Irf7, and Tnf mRNAs was upregulated over baseline control at 3 days post-infection (p.i.) only in young mice, but old mice expressed more Ifnl than young mice 7 days p.i. Gene arrays showed down-regulation of the Epigenetic Regulation, Insulin Signaling, and Neurons and Neurotransmission pathways in old mice 3 days p.i. while young mice demonstrated no change or induction of these pathways at the same time point. IPA revealed marked baseline differences between old and young mice. Gene expression related to Cognitive Impairment, Memory Deficits and Learning worsened in old mice relative to young mice during IAV infection. Aged mice demonstrate more severe changes in gene expression related to memory loss and cognitive dysfunction by IPA. Conclusions These data suggest the genes and pathways related to learning and cognitive performance that were worse at baseline in old mice were further worsened by IAV infection, similar to old patients. Early events in the brain triggered by IAV infection portend downstream neurocognitive pathology in old adults.

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“…On the contrary, in the amyloidogenic pathway, β-secretase cleaves APP at the N-terminus of the Aβ sequence, originating sAPPβ and transmembrane βCTF. Therefore, upon the subsequent action of γ-secretase, the cleavage of βCTF, but not that of αCTF, results in the production of Aβ [ 23 , 24 ]. The processing of βCTF by γ-secretase occurs at different sites, thus yielding many Aβ peptides of variable length, with Aβ 40 being the most abundant form in the brain, followed by Aβ 38 and Aβ 42 [ 25 ].…”

Section: The Amyloid Cascade Hypothesis: From Plaques To Soluble Olig...mentioning

confidence: 99%

Anti-Amyloid Therapies for Alzheimer’s Disease and the Amyloid Cascade Hypothesis

Fedele

2023

IJMS

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Over the past 30 years, the majority of (pre)clinical efforts to find an effective therapy for Alzheimer’s disease (AD) focused on clearing the β-amyloid peptide (Aβ) from the brain since, according to the amyloid cascade hypothesis, the peptide was (and it is still considered by many) the pathogenic determinant of this neurodegenerative disorder. However, as reviewed in this article, results from the numerous clinical trials that have tested anti-Aβ therapies to date indicate that this peptide plays a minor role in the pathogenesis of AD. Indeed, even Aducanumab and Lecanemab, the two antibodies recently approved by the FDA for AD therapy, as well as Donanemab showed limited efficacy on cognitive parameters in phase III clinical trials, despite their capability of markedly lowering Aβ brain load. Furthermore, preclinical evidence demonstrates that Aβ possesses several physiological functions, including memory formation, suggesting that AD may in part be due to a loss of function of this peptide. Finally, it is generally accepted that AD could be the result of many molecular dysfunctions, and therefore, if we keep chasing only Aβ, it means that we cannot see the forest for the trees.

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Amyloid Precursor Protein: A Regulatory Hub in Alzheimer's Disease

Cited by 6 publications

References 210 publications

Tailored Melatonin- and Donepezil-Based Hybrids Targeting Pathognomonic Changes in Alzheimer’s Disease: An In Vitro and In Vivo Investigation

Tailored Melatonin- and Donepezil-Based Hybrids Targeting Pathognomonic Changes in Alzheimer’s Disease: An In Vitro and In Vivo Investigation

Influenza virus infection exacerbates gene expression related to neurocognitive dysfunction in brains of old mice

Anti-Amyloid Therapies for Alzheimer’s Disease and the Amyloid Cascade Hypothesis

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