Map of the Alzheimer site

sAPP is the soluble N-terminal fragments derived from the alpha-secretase cleavage, and these fragments can be produced from APLP as well as APP. sAlpha-APP was reported to protect neurons from ischemic injury or enhance recovery from ischemic injury in adult animals (Bowes et al., 1994; Smith-Swintosky et al., 1994) and showed the effects on ion fluxes (Fraser et al., 1997).

In addition, salpha-APP can stimulate neurite outgrowth in PC12 cells, promote the proliferation of fibroblasts, and protect cultured neurons from metabolic and excitotoxic insults (Mattson et al., 1993). See also Wang R, A novel neurotrophic peptide: APP63-73., Neuroreport 2004 Dec;15(17):2677-80 PubMed Abstract

Regarding signal transudation pathway, sAlpha-APP is implicated to play a role in activation of NF-kappaB (Barger and Mattson, 1996), phospholipaseC/protein kinase C, inositol trisphosphate (Ishiguro et al., 1998), and extracellular signal-regulated protein kinase (Greenberg et al., 1994)

Many studies have shown that acetylcholine receptor agonists affect Abeta accumulation by modulating APP metabolism.

The cholinergic stimulation elicits an increase in sAlpha-APP release, which is known to have potent neurotrophic and neuroprotective effects (Mattson et al.,1993) and thus leads to the reduction of toxic Abeta generation (Rossner et al., 1998). In HEK cells transfected with human gene for M1 and M3 muscarinic acetylcholine receptor, it was proved first that amyloidogenic or nonamyloidogenic release of APP is mediated by stimulation of muscarinic acetylcholine receptor and coupled with protein kinase (Buxbaum et al., 1992; Nitsch et al., 1992; Marambaud et al., 1998b, 1999). In subsequent studies, the evidence that APP secretion and processing is regulated by cholinergic stimulation has been clarified further. Cholinergic agonists such as acetylcholine, nicotine,or carbacol stimulated the release of soluble sAPP in primary-cultured chromaffin cells (Efthimiopoulos et al., 1996). Cortical nonamyloidogenic APP processing under basal forebrain cholinergic control is mediated through muscarinic receptor (Rossner et al., 1997).

Therefore, proper stimulation of cholinergic receptor in the brain can increase secretion of the soluble form of APP and thus lead to a reduction in production and toxicity of Abeta .

The role of nicotinic acetylcholine receptor (nAChR) in APP secretary pathway has also been determined to develop a novel nAChR antagonist that is able to reduce the A_ burden. There is accumulating in vitro evidence that stimulation of the nicotinic receptor might play an important role in neuroprotection against A_-induced cytotoxicity and might exert AD pathogenesis to slow onset (Kihara et al., 1997, 1998; Zamani et al., 1997; Shimohama and Kihara, 2001).

We confirmed that treatment of PC12 cells with nicotine increases the release of a secreted form of APP_, and the effect is attenuated by the modulation of calcium entry through neuronal nAChR (Kim et al., 1997). Moreover, our recent study showed protective effects of nicotineon cytotoxicity induced by toxic carboxyl-terminal fragments of APP (Seo et al., 2001). Further extensive study is needed to elucidate which pathway is involved in nicotine-mediated APP metabolism in AD, although two controversial findings indicate that the protectiverole of nicotine is correlated with _-sheet conformationalchange of A_ (Salomon et al., 1996; Kihara et al., 1999). A pilot clinical finding showed that short-term administration of nicotine increased perceptual and visual attention in patients with AD, indicating that nicotine may have some beneficial effect for acquiring the information in AD despite no improvement of short-term memory function (Jones et al., 1992). To assess the short-term effects of ABT-418, a novel nicotinic receptor, behavioral changes were investigated in patients with early AD (Potter et al., 1999). Verbal and nonverbal learning and memory ability were significantly improved after three doses of ABT-418 (6, 12, and 23 mg/kg) on each of 4 days. These results strongly implicate that nicotine or nicotinic receptor agonist might have therapeutic potential for AD by reducing amyloidogenic processing of APP.

Because it has been reported that acetylcholinesterase (AChE) may possess nonamyloidogenic _-secretase activity cleaving APP from the membrane releasing the soluble ectodomain (Small et al., 1991), several kinds of AChEIs have also been examined to determine whether they can affect APP metabolism. Mori et al. (1995) demonstrated that AChEIs including physostigmine, heptylphysostigmine, and 2,2-dichlroro-vinyldimethylphosphate significantly enhance the release of s_-APP (Mori et al., 1995) in brain slice of rat. Short- and long-term treatment of metrifonate and dichlorvos, another active cholinesterase inhibitor, induced an increased secretion of the soluble fragment of APP, s_-APP, via activation of PKC-coupled muscarinic receptors without changes in APP expression (Pakaski et al., 2000; Racchi et al., 2001)

On the contrary, the FDA-approved AD drug tacrine might inhibit nonamyloidogenic processing of APP and thus contribute to A_ deposition in brain with AD (Lahiri et al., 1994; Chong and Suh, 1996). Subsequent study showed that tacrine could reduce the release of s_-APP and total A_ in the conditioned medium of human neuroblastoma cell, not accompanying by increase in _-APP synthesis and cell death (Lahiri et al., 1998; Lahiri et al., 2000). They demonstrated that tacrine might affect the trafficking of _-APP and/or increase intracellular proteolysis. However, the detailed influence of tacrine on APP secretion remains to be studied further.

The first clinical study investigated whether another available acetylcholinesterase inhibitor, donepezil (5mg/day for 30 days), can affect the ratio of platelet APP forms in patients with AD (Borroni et al., 2001). The ratio of APP forms is restored to control level, and cognitive ability is improved in the donepezil-treated patient with AD. Dehydroevodiamine HCl (DHED), a new potential drug for AD and vascular dementia (Park et al., 1996, 2000), has been found to increase sAlpha-APP release from PC12 cells and to protect neurons against Abeta or carboxyl terminal peptide (CT)-induced toxicity (unpublished data).

Thus, the administration of cholinergic agonist or AChE inhibitor to patients with AD may produce the favorable clinical results in ameliorating not only ACh-dependent cognitive function but also AD pathogenesis by the modulation of APP metabolism.

From Suh and Checler, 2002