Beyond the Hypothesis of Serum Anticholinergic Activity in Alzheimer's Disease: Acetylcholine Neuronal Activity Modulates Brain-Derived Neurotrophic Factor Production and Inflammation in the Brain

Abstract

The brain of Alzheimer's disease (AD) patients is characterized by neurodegeneration, especially an acetylcholine (ACh) neuronal deficit with accumulation of β-amyloid protein, which leads to oxygen stress and inflammation. The active oxygen directly damages the neuron by increasing intracellular Ca²⁺. The inflammation is due to activation of the microglia, thereby producing cytokines which inhibit the production of brain-derived neurotrophic factor (BDNF). As the BDNF acts by neuronal protection, synaptogenesis and neurogenesis, the reduction of BDNF in the brain of AD patients worsens the symptoms of AD. On the other hand, treatment of AD patients with a cholinesterase inhibitor enhances ACh activity and inhibits inflammation. Then the expression of BDNF is restored and neuroprotection reestablished. However, there are several reports which showed controversial results concerning the relationship between BDNF and AD. We speculate that BDNF is related to some neurocognitive process and reflects neuronal activity in other neurodegenerative and neuropsychiatric disorders and that in the mild cognitive impairment stage, BDNF and choline acetyltransferase (ChAT) activities are hyperactivated because of a compensatory mechanism of AD pathology. In contrast, in the mild stage of AD, BDNF and ChAT activity are downregulated.

Clinical and Environmental Correlates of Serum BDNF: A Descriptive Study with Plausible Implications for AD Research

“…In rats, for example, peripheral immune activation significantly decreased BDNF mRNA levels in the hippocampus and cortical regions [62–64]. These findings have led to the hypothesis that brain inflammatory response to aging and immune challenge may cause a reduction in BDNF levels, a process that may lead to impairment in brain plasticity and cognition [25–27]. In this context, our finding that increased levels of TNF-α are related to low BDNF levels further supports this hypothesis, and may indicate that the previous observations may be valid also in humans and when serum rather than brain tissue levels are measured.…”

“…Effect modification by sex has been previously demonstrated in other studies, [20, 21] and can be explained by BDNF interaction with estrogen [22], progesterone [23, 24], and other sex-related hormones. The complexity of the underlying mechanisms involving BDNF is also indicated by the emerging evidence of common influences of amyloid β and cytokines levels on BDNF production, and the hypothesis that BDNF levels may at least partly explain the link between inflammation and brain function [25–27]. Furthermore, alterations in BDNF circulating levels are not a special feature of neurodegenerative diseases but have also been linked with cardiovascular disease [28], type 2 diabetes [29] and the metabolic syndrome [30], which, in turn, confer risk for AD.…”

Anti-inflammatory and detoxification activities of some Ipomoea species determined by ion channel inhibition and their phytochemical constituents

“…These high oleamide quantities are expected to be expressed in a single unit, which is expected to be one of the active phytochemicals [9]. However, the experiment on oleamide activity merits further study given its use for treatments of Alzheimer's disease, stress, deep sleep, and appetite induction [10]. Recently, the anti-inflammatory effect of oleamide has been shown [11][12][13].…”

Screening of phytochemicals and toxicity of medicinal plants,Dilleniaspecies, reveals potential natural product resources

“…As per known oleamide activities, it enhances memory function, promotes sleep and acts as a chemopreventive agent against Alzheimer's disease (Hachisu et al, ). Accordingly, it was discovered in high amounts in the nine studied species.…”