FOXO1 locus and acetylcholinesterase inhibitors in elderly patients with Alzheimer&amp;rsquo;s disease

Paroni, Giulia; Seripa, Davide; Fontana, Andrea; Gravina, Carolina; Urbano, María Amor; Cascavilla, Leandro; Pellegrini, Fabio; Greco, Antonio

doi:10.2147/cia.s64758

Cited by 15 publications

(6 citation statements)

References 36 publications

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“…FOXO1 gene encodes transcription factor that plays a role in autophagy modulation in neurons ( Xu et al, 2011 ). FOXO1 mutation rs7981045 was associated with response of AD patients to a treatment based on acetylcholinesterase inhibitors ( Paroni et al, 2014 )…”

Section: Biological Mechanisms Linking Autophagy and Admentioning

confidence: 99%

Autophagy and Alzheimer’s Disease: From Molecular Mechanisms to Therapeutic Implications

Uddin

Stachowiak

Mamun

et al. 2018

Front. Aging Neurosci.

330

247

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Alzheimer’s disease (AD) is the most common cause of progressive dementia in the elderly. It is characterized by a progressive and irreversible loss of cognitive abilities and formation of senile plaques, composed mainly of amyloid β (Aβ), and neurofibrillary tangles (NFTs), composed of tau protein, in the hippocampus and cortex of afflicted humans. In brains of AD patients the metabolism of Aβ is dysregulated, which leads to the accumulation and aggregation of Aβ. Metabolism of Aβ and tau proteins is crucially influenced by autophagy. Autophagy is a lysosome-dependent, homeostatic process, in which organelles and proteins are degraded and recycled into energy. Thus, dysfunction of autophagy is suggested to lead to the accretion of noxious proteins in the AD brain. In the present review, we describe the process of autophagy and its importance in AD. Additionally, we discuss mechanisms and genes linking autophagy and AD, i.e., the mTOR pathway, neuroinflammation, endocannabinoid system, ATG7, BCL2, BECN1, CDK5, CLU, CTSD, FOXO1, GFAP, ITPR1, MAPT, PSEN1, SNCA, UBQLN1, and UCHL1. We also present pharmacological agents acting via modulation of autophagy that may show promise in AD therapy. This review updates our knowledge on autophagy mechanisms proposing novel therapeutic targets for the treatment of AD.

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Section: Biological Mechanisms Linking Autophagy and Admentioning

confidence: 99%

Autophagy and Alzheimer’s Disease: From Molecular Mechanisms to Therapeutic Implications

Uddin

Stachowiak

Mamun

et al. 2018

Front. Aging Neurosci.

330

247

View full text Add to dashboard Cite

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“…FOXO1 is implicated in the cellular response to oxidative stress, and it has been linked to AD through brain insulin resistance. It has been suggested that AChEI may protect cholinergic neurons by enhancing antioxidant activity, and it is possible that the GG genotype of FOXO1 directly contrasts this putative mechanism through increased production of reactive oxygen species (Paroni et al, 2014 ). However, further studies are needed to confirm this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

“…This could be explained by the premise above, since younger subjects (with "true" AD pathology) would respond to AChEI in the typical period of months, while older subjects (possibly including LATE patients) would show a slower decline over years, when the effect of AChEI is expected to be clinically negligible (Boccardi et al, 2017). Similar considerations may be made for primary age-related tauopathy (PART), introduced by Crary et al (2014).…”

Section: Demographic Factors: Age Gender Racementioning

confidence: 92%

Predictors of response to acetylcholinesterase inhibitors in dementia: A systematic review

et al. 2022

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BackgroundThe mainstay of therapy for many neurodegenerative dementias still relies on acetylcholinesterase inhibitors (AChEI); however, there is debate on various aspects of such treatment. A huge body of literature exists on possible predictors of response, but a comprehensive review is lacking. Therefore, our aim is to perform a systematic review of the predictors of response to AChEI in neurodegenerative dementias, providing a categorization and interpretation of the results.MethodsWe conducted a systematic review of the literature up to December 31st, 2021, searching five different databases and registers, including studies on rivastigmine, donepezil, and galantamine, with clearly defined criteria for the diagnosis of dementia and the response to AChEI therapy. Records were identified through the string: predict*AND respon*AND (acetylcholinesterase inhibitors OR donepezil OR rivastigmine OR galantamine). The results were presented narratively.ResultsWe identified 1,994 records in five different databases; after exclusion of duplicates, title and abstract screening, and full-text retrieval, 122 studies were finally included.DiscussionThe studies show high heterogeneity in duration, response definition, drug dosage, and diagnostic criteria. Response to AChEI seems associated with correlates of cholinergic deficit (hallucinations, fluctuating cognition, substantia innominate atrophy) and preserved cholinergic neurons (faster alpha on REM sleep EEG, increased anterior frontal and parietal lobe perfusion after donepezil); white matter hyperintensities in the cholinergic pathways have shown inconsistent results. The K-variant of butyrylcholinesterase may correlate with better response in late stages of disease, while the role of polymorphisms in other genes involved in the cholinergic system is controversial. Factors related to drug availability may influence response; in particular, low serum albumin (for donepezil), CYP2D6 variants associated with reduced enzymatic activity and higher drug doses are the most consistent predictors, while AChEI concentration influence on clinical outcomes is debatable. Other predictors of response include faster disease progression, lower serum cholesterol, preserved medial temporal lobes, apathy, absence of concomitant diseases, and absence of antipsychotics. Short-term response may predict subsequent cognitive response, while higher education might correlate with short-term good response (months), and long-term poor response (years). Age, gender, baseline cognitive and functional levels, and APOE relationship with treatment outcome is controversial.

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“…Oxidative stress and AD are linked together by forkhead box O1 (FOXO1) ( Paroni et al, 2014 ; Zhang W. et al, 2020 ). FOXO1 overexpression reduced both tau phosphorylation and Aβ expression ( Zhang W. et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Network pharmacology identify intersection genes of quercetin and Alzheimer’s disease as potential therapeutic targets

Wei

Zhu

et al. 2022

Front. Aging Neurosci.

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BackgroundCurrently, there are no efficient therapies for Alzheimer’s disease (AD) among the elderly, although it is the most common etiology of dementia among the elderly. Quercetin, which has a variety of therapeutic properties, may pave the way for novel approaches to AD treatment. In the AD patients’ frontal cortex, current study aims to identify the potential mechanisms of quercetin’s pharmacological targets.Materials and methodsThe pharmacological targets of quercetin have been studied from DrugBank and SwissTarget. In order to distinguish AD-associated genes targeted by quercetin (Q-ADGs), we utilized an integrated intersection of gene expressions of the frontal cortex in combination with transcriptome analysis. To detect cortex-related Q-ADGs and immune-related Q-ADGs, a drug screening database and the immune infiltration analysis was utilized. The Q-ADGs were then linked with the AD severity scores (MMSE scores) to find severity-associated Q-ADGs. In addition, the miRNA-seq datasets were examined to identify severity-associated Q-ADG-miRNAs. Twelve genes, more frequently related to AD by previous studies among all the genes identified in the present study, were subjected to the verification of qRT-PCR in AD cell model.ResultsIn the frontal lobe of AD, 207 Q-ADGs were discovered and found that axonogenesis, glial differentiation, and other biological processes had been enriched. There were 155 immune-related Q-ADGs (e.g., COX2, NOS2, HMGB1) and 65 cortex-related Q-ADGs (e.g., FOXO1, CXCL16, NOTCH3). Sixteen Q-ADGs (e.g., STAT3, RORA, BCL6) and 28 miRNAs (e.g., miR-142-5p, miR-17-5p) were found to be related to MMSE scores. In the qRT-PCR results, six out of twelve genes were significantly regulated by quercetin. DYRK1A, FOXO1, NOS2, NGF, NQO1, and RORA genes were novel target of quercetin in AD. DYRK1A, NOS2, and NQO1 genes targeted by quercetin have benefits in the treatment of AD. However, FOXO1, NGF, and RORA genes targeted by quercetin might have a negative impact on AD.ConclusionThe role of quercetin in AD appears to be multifaceted, and it can affect patients’ frontal cortex in a variety of pathways, such as axonogenesis, immune infiltration, and glial cell differentiation. DYRK1A, NOS2, and NQO1 might be potential novel effective drug targets for quercetin in AD.

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FOXO1 locus and acetylcholinesterase inhibitors in elderly patients with Alzheimer’s disease

Cited by 15 publications

References 36 publications

Autophagy and Alzheimer’s Disease: From Molecular Mechanisms to Therapeutic Implications

Autophagy and Alzheimer’s Disease: From Molecular Mechanisms to Therapeutic Implications

Predictors of response to acetylcholinesterase inhibitors in dementia: A systematic review

Network pharmacology identify intersection genes of quercetin and Alzheimer’s disease as potential therapeutic targets

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