Role of Cholinergic Signaling in Alzheimer’s Disease

Chen, Zhi-Ru; Huang, Jiabao; Yang, Shaoyu; Hong, Fen-Fang

doi:10.3390/molecules27061816

Cited by 270 publications

(135 citation statements)

References 139 publications

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“…Nevertheless, in both EFV and 8,14-dihydroxyEFV-treated mice, increased production of acetyl-CoA led to increased production of Ach. This is a new and important insight into the beneficial treatment effect as the brain Ach levels are decreased in AD due to selective degeneration of cholinergic neurons [ 34 ]. The latter leads to impaired cholinergic neurotransmission and contributes to cognitive decline in AD [ 35 ].…”

Section: Resultsmentioning

confidence: 99%

Increased Acetylcholine Levels and Other Brain Effects in 5XFAD Mice after Treatment with 8,14-Dihydroxy Metabolite of Efavirenz

Mast

Pikuleva

2022

IJMS

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Efavirenz (EFV), an FDA-approved anti-HIV drug, has off-target binding to CYP46A1, the CNS enzyme which converts cholesterol to 24-hydroxycholesterol. At small doses, EFV allosterically activates CYP46A1 in mice and humans and mitigates some of the Alzheimer’s disease manifestations in 5XFAD mice, an animal model. Notably, in vitro, all phase 1 EFV hydroxymetabolites activate CYP46A1 as well and bind either to the allosteric site for EFV, neurotransmitters or both. Herein, we treated 5XFAD mice with 8,14-dihydroxyEFV, the binder to the neurotransmitter allosteric site, which elicits the highest CYP46A1 activation in vitro. We found that treated animals of both sexes had activation of CYP46A1 and cholesterol turnover in the brain, decreased content of the amyloid beta 42 peptide, increased levels of acetyl-CoA and acetylcholine, and altered expression of the brain marker proteins. In addition, male mice had improved performance in the Barnes Maze test and increased expression of the acetylcholine-related genes. This work expands our knowledge of the beneficial CYP46A1 activation effects and demonstrates that 8,14-dihydroxyEFV crosses the blood–brain barrier and has therapeutic potential as a CYP46A1 activator.

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Section: Resultsmentioning

confidence: 99%

Increased Acetylcholine Levels and Other Brain Effects in 5XFAD Mice after Treatment with 8,14-Dihydroxy Metabolite of Efavirenz

Mast

Pikuleva

2022

IJMS

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“…Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common type of dementia, closely related to genetic factors and age. It predominantly affects neocortical regions and is characterized by progressively episodic memory loss, significant behavioral changes, and a very high mortality rate [ 90 , 104 , 105 , 106 , 107 , 108 , 109 , 110 ]. Nevertheless, the pathogenesis of AD remains elusive and mainly rests on the observed accumulations of amyloid beta into plaques and hyperphosphorylated tau protein aggregates.…”

Section: Neurotransmitter Disorders Of the Cnsmentioning

confidence: 99%

“…In more detail, an abnormal cholinergic system regulates and promotes changes in the metabolism of amyloid precursor protein and tau phosphorylation, triggering neurotoxicity, neuroinflammation, and neuronal death. Furthermore, as acetylcholine can regulate the normal cholinergic signal transduction (associated with learning and memory), its low levels in AD patients are no surprise, being manifested through damaged cholinergic signal transduction and cognitive impairment [ 11 , 104 ]. In particular, the cholinergic neurons forming the nucleus basalis of Meynert are specifically degenerated, leading to memory loss in individuals diagnosed with AD [ 115 ].…”

Section: Neurotransmitter Disorders Of the Cnsmentioning

confidence: 99%

Neurotransmitters—Key Factors in Neurological and Neurodegenerative Disorders of the Central Nervous System

Teleanu

Niculescu

Roza

et al. 2022

IJMS

170

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Neurotransmitters are molecules that amplify, transmit, and convert signals in cells, having an essential role in information transmission throughout the nervous system. Hundreds of such chemicals have been discovered in the last century, continuing to be identified and studied concerning their action on brain health. These substances have been observed to influence numerous functions, including emotions, thoughts, memories, learning, and movements. Thus, disturbances in neurotransmitters’ homeostasis started being correlated with a plethora of neurological and neurodegenerative disorders. In this respect, the present paper aims to describe the most important neurotransmitters, broadly classified into canonical (e.g., amino acids, monoamines, acetylcholine, purines, soluble gases, neuropeptides) and noncanonical neurotransmitters (e.g., exosomes, steroids, D-aspartic acid), and explain their link with some of the most relevant neurological conditions. Moreover, a brief overview of the recently developed neurotransmitters’ detection methods is offered, followed by several considerations on the modulation of these substances towards restoring homeostasis.

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“…It is present in both the peripheral and central nervous systems and is associated with learning abilities, cognitive functions, and memory [ 25 ]. These actions are conducted by basal forebrain cholinergic neurons (BFCN), which are less present in AD patients because of neuron degeneration [ 26 ]. It correlates with the cholinergic hypothesis in which impairment of cognitive functions is obtained through cholinergic neurons degradation and, as a result, disturbances in cholinergic neurotransmission in the disease-affected brain [ 27 ].…”

Section: Existing Drug Therapiesmentioning

confidence: 99%

New Possibilities in the Therapeutic Approach to Alzheimer’s Disease

Doroszkiewicz

Mroczko

2022

IJMS

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Despite the fact that Alzheimer’s disease (AD) is the most common cause of dementia, after many years of research regarding this disease, there is no casual treatment. Regardless of the serious public health threat it poses, only five medical treatments for Alzheimer’s disease have been authorized, and they only control symptoms rather than changing the course of the disease. Numerous clinical trials of single-agent therapy did not slow the development of disease or improve symptoms when compared to placebo. Evidence indicates that the pathological alterations linked to AD start many years earlier than a manifestation of the disease. In this pre-clinical period before the neurodegenerative process is established, pharmaceutical therapy might prove invaluable. Although recent findings from the testing of drugs such as aducanumab are encouraging, they should nevertheless be interpreted cautiously. Such medications may be able to delay the onset of dementia, significantly lowering the prevalence of the disease, but are still a long way from having a clinically effective disease-modifying therapy.

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Role of Cholinergic Signaling in Alzheimer’s Disease

Cited by 270 publications

References 139 publications

Increased Acetylcholine Levels and Other Brain Effects in 5XFAD Mice after Treatment with 8,14-Dihydroxy Metabolite of Efavirenz

Increased Acetylcholine Levels and Other Brain Effects in 5XFAD Mice after Treatment with 8,14-Dihydroxy Metabolite of Efavirenz

Neurotransmitters—Key Factors in Neurological and Neurodegenerative Disorders of the Central Nervous System

New Possibilities in the Therapeutic Approach to Alzheimer’s Disease

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