Hypothesis of Endogenous Anticholinergic Activity in Alzheimer's Disease

Konishi, Kimiko; Hori, Koji; Tani, Masayuki; Tomioka, Haruaki; Kitajima, Yuriko; Akashi, Norihisa; Inamoto, Atsuko; Kurosawa, Kenzo; Yuda, Haijime; Hanashi, Takahiro; Ouchi, Hiromi; Hosoi, Misa; Hachisu, Mitsugu

doi:10.1159/000381511

Cited by 15 publications

(15 citation statements)

References 30 publications

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“…, for example, found that a long‐term blockade of the muscarinic receptors, as an effect of anticholinergic drugs, increases the presence of amyloid‐β peptide in the cortex, hippocampus and amygdala. Consequently, since Alzheimer’s Disease reflects lower cholinergic activity, the use of anticholinergic drugs with central action might affect cognitive performance .…”

Section: Discussionmentioning

confidence: 99%

Role of anticholinergic burden in primary care patients with first cognitive complaints

Grande

Tramacere

Vetrano

et al. 2017

Euro J of Neurology

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Section: Discussionmentioning

confidence: 99%

Role of anticholinergic burden in primary care patients with first cognitive complaints

Grande

Tramacere

Vetrano

et al. 2017

Euro J of Neurology

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“…AD is a neurodegenerative disease characterized by a progressive loss of learning and memory as well as neuronal death. The hippocampus, the main brain region involved in memory processing, is influenced by cholinergic modulation [ 95 ]. One of the well characterized anomalies associated with neurotransmitter alterations is the degeneration of cholinergic neurons in the nucleus basalis of Meynert and the loss of cholinergic inputs to the neocortex and hippocampus.…”

Section: The Cholinergic Hypothesismentioning

confidence: 99%

Current Research Therapeutic Strategies for Alzheimer’s Disease Treatment

et al. 2016

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Alzheimer's disease (AD) currently presents one of the biggest healthcare issues in the developed countries. There is no effective treatment capable of slowing down disease progression. In recent years the main focus of research on novel pharmacotherapies was based on the amyloidogenic hypothesis of AD, which posits that the beta amyloid (Aβ) peptide is chiefly responsible for cognitive impairment and neuronal death. The goal of such treatments is (a) to reduce Aβ production through the inhibition of β and γ secretase enzymes and (b) to promote dissolution of existing cerebral Aβ plaques. However, this approach has proven to be only modestly effective. Recent studies suggest an alternative strategy centred on the inhibition of the downstream Aβ signalling, particularly at the synapse. Aβ oligomers may cause aberrant N-methyl-D-aspartate receptor (NMDAR) activation postsynaptically by forming complexes with the cell-surface prion protein (PrPC). PrPC is enriched at the neuronal postsynaptic density, where it interacts with Fyn tyrosine kinase. Fyn activation occurs when Aβ is bound to PrPC-Fyn complex. Fyn causes tyrosine phosphorylation of the NR2B subunit of metabotropic glutamate receptor 5 (mGluR5). Fyn kinase blockers masitinib and saracatinib have proven to be efficacious in treating AD symptoms in experimental mouse models of the disease.

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Section: Opinionmentioning

confidence: 99%

“…Based on this speculation, we propose "the hypothesis of endogenous appearance of AA in AD" [6]. That is, when the downregulation of ACh reaches critical level, AA appears endogenously by way of hyperactivation of inflammatory system and accelerates amyloid pathology [5,6]. Because the factors those cause AA and now reported three other than downregulation of ACh, i.e., medication [7], physical illness [8] and mental stress [9].…”

Section: Opinionmentioning

confidence: 99%

Role of Cholinergic System in Neuropsychiatric Disorders

Hori¹

2017

Anat Physiol

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OpinionNeedless to say acetylcholine (ACh) is relared with cognitive function [1]. However, ACh also suppresses inflammatory system [2], therefore, downregulation of ACh not only causes cognitive dysfunction, but also accelerates inflammatory system. This hyperactivity of inflammatory system is related with various neuropsychiatric disorders including Alzheimer's disease (AD) [3] and depression [4].Moreover, we also speculate this hyperactivity of inflammatory system also induces anticholinergic activity (AA) and this AA accelerates amyloid pathology [5]. Based on this speculation, we propose "the hypothesis of endogenous appearance of AA in AD" [6]. That is, when the downregulation of ACh reaches critical level, AA appears endogenously by way of hyperactivation of inflammatory system and accelerates amyloid pathology [5,6]. Because the factors those cause AA and now reported three other than downregulation of ACh, i.e., medication [7], physical illness [8] and mental stress [9]. Therefore, it is natural that when based on the small amount of deterioration of ACh other AA insert is added, AA also appears [10]. In fact, we showed the patient with AD at MCI level whose serum anticholinergic activity might be positive caused by both small amount of down regulation of ACh and mental stress [11]. Moreover, overburden of cholinergic system might also attribute to the appearance of AA because ACh is no more upregulated in order to compensate for AA insert (upregulation of ACh). Therefore there might be a possibility of the appearance of AA in other disease than AD. We also speculate there might be a possibility of the endogenous appearance of AA in depression and Lewy body disease (LBD). Increased activity of the hypothalamic-pituitary-adrenal (HPA) axis and the small amount of downregulation of ACh. It is plausible to conclude that in depression and LBD AA might appear endogenously [12,13]. In depression, the cholinergic system is burdened secondarily to the underlying depressive pathology. During remission, activity of cholinacetyl transferase (ChAT), an enzyme that produces ACh, might be sufficiently upregulated to compensate for the cholinergic burden caused by depressive pathology. However, at the pathological state (depressive state), more upregulation of ACh is not impossible because the ChAT activity is already upregulate. Therefore, in depression there might be a possibility of endogenous appearance of AA [14]. In delirium, we also speculate there might be a possibility of the appearance of AA in delirium. In delirium, increased activity of the HPA axis by exogenous factor, i.e., physical illness, medication or mental stress and the small amount of downregulation of ACh caused by aging or AD, AA also appears.From these considerations we speculate that at least in AD, LBD and depression, the progression of disease might be related with AA at least late sage. Alternatively at late phase of AD, LBD and depression, main pathology might be amyloid pathology. We propose the concept of "anticholinergic spectrum disor...

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Hypothesis of Endogenous Anticholinergic Activity in Alzheimer's Disease

Cited by 15 publications

References 30 publications

Role of anticholinergic burden in primary care patients with first cognitive complaints

Role of anticholinergic burden in primary care patients with first cognitive complaints

Current Research Therapeutic Strategies for Alzheimer’s Disease Treatment

Role of Cholinergic System in Neuropsychiatric Disorders

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