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    • Although the mechanisms of APP secretion are

    2023-01-24

    Although the mechanisms of APP secretion are well characterised (for review see Ref. [1]), production of soluble AChE species is less well understood although we have reported that a metalloproteinase can shed AChE similarly to APP [16], [17]. Recently it has also been demonstrated that cellular presenilin-1 (PS1) levels correlate with AChE expression [21] and that both membrane-bound and soluble AChE can regulate PS1 and γ-secretase activity thereby modulating APP cleavage and release [22]. Furthermore, PS1 interacts with acetylcholinesterase altering its enzymatic activity and glycosylation [23], and influences processing of the acetylcholinesterase membrane anchor PRiMA [24].
    The cholinergic system and pathogenesis of AD The basal forebrain cholinergic system is strongly linked to AD and there are convincing data linking cholinergic hypofunction with cognitive decline related to age and neurodegeneration [25], [26], [27]. For yet unknown reasons, cholinergic neurons of the basal forebrain are specifically affected by AD pathology where a cholinergic deficit was observed both in early onset and the advanced stages of the disease [27], [28], [29], subsequently leading to the development of anti-cholinesterases as therapeutic agents in AD [30], [31]. The early reports on the neurochemistry of AD have also shown specific and significant decline in AChE activity in the affected areas of the ag1478 mg not affecting other enzyme systems [32]. Using an animal model it was later demonstrated that introducing the gene bearing human APP751 carrying the Swedish double mutation resulted in development of a cholinergic deficit and neuronal loss in the cortex and hippocampus which was increased when such mice were crossbred with individuals bearing a human PS1 mutated gene [33]. With ageing, cholinergic neurones were shown to become more sensitive to the harmful effects of Aβ resulting in cholinergic deficit in the hippocampus and cognitive deficit [34], [35]. This suggests ag1478 mg that the altered APP metabolism characteristic of AD pathology affects the cholinergic system in the brain and its major enzyme, AChE. It is becoming more apparent that acetylcholine (ACh) and its principal hydrolysing enzyme AChE, have various regulatory functions affecting neuronal functioning and survival [12], [14], [36], [37], [38]. In neurospheres derived from human embryonic cells, levels of cholinergic enzymes were shown to be reduced by exogenous fibrillar Aβ resulting in lower levels of acetylcholine, which suggest that Aβ can decrease neurogenesis by promoting a microenvironment favouring hypo-cholinergic signalling and gliogenesis [39]. While Aβ seems to affect cholinergic neurones in the brain cholinergic agents, in turn, were demonstrated to affect various brain functions including formation of Aβ [40]. In particular, non-catalytic functions of cholinesterase inhibitors were shown to alter APP metabolism which might thereby affect the process of Aβ deposition [41]. It has been known for some time that ACh and nicotinic ACh receptor (nAChR) density decrease with progression of AD [42], [43]. Moreover, Aβ was shown to bind and modulate nAChRs [44]. This led to the conclusion that nAChR ligands, including nicotine, might be used as potential drug targets for AD [45]. Moreover, modulation of APP processing and Aβ levels in the brain via cholinergic treatment strategies based on nicotinic or M1 muscarinic agonists versus other cholinergic treatments might represent another effective strategy [46], [47]. This is particularly relevant for designing AD therapy since long-term treatment of patients with cholinesterase inhibitors such as donepezil was shown to result in an increased AChE expression which might initiate increased Aβ aggregation [21], [48]. Based on these findings, Dareh-Shori and colleagues suggested that combination of donepezil with a low dose of an irreversible inhibitor, which produces stable AChE inhibition with no significant alteration in AChE protein levels, could be a more effective strategy [49]. Apart from altering AChE activity and metabolism, cholinesterase inhibitors were shown to differentially affect APP processing [21], [41], [50] which, in turn, might have implications for amyloid metabolism and disease progression.