A Short Review
M. Reza Zamani and Yvonne S. Allen
Two features of Alzheimer’s disease (AD) areb-amyloid protein (bAP) deposition and a severe cholinergic deficit.
b-Amyloid protein is a 39 – to 43–amino acid transmem-brane fragment of a larger precursor molecule, amyloid precursor protein. It is a major constituent of senile plaque, a neuropathologic hallmark of AD, and has been shown to be neurotoxic in vivo and in vitro. The cholin-ergic neurotransmission system is seen as the primary target of AD. However, other systems are also found to show functional deficit. An association between cholin-ergic deficit andbAP is suggested by a negative correla-tion between cigarette smoking and AD. Evidence hitherto suggests that bAP causes neuronal death possibly via apoptosis by disrupting calcium homeostasis, which may involve direct activation or enhancement of ligand-gated or voltage-dependent calcium channels. Selective second messengers such as protein kinases are triggered that signal neuronal death. Nicotine or acetylcholinesterase inhibitors can partially prevent the neurotoxicity ofbAP in vivo and in vitro. However, the exact mechanism by which nicotine provides its protective effects is not fully understood, but clearly there are protective roles for nicotine. Here, some aspects of bAP neurotoxicity and nicotinic intervention as a protective agent are discussed. Biol Psychiatry 2001;49:221–232 © 2001 Society of Bio-logical Psychiatry
Key Words:b-Amyloid protein, neurotoxicity, neuropro-tection, nicotine, acetylcholine receptor
Introduction
E
arlier findings that cigarette smoking is negatively correlated with Parkinson’s disease (Bharucha et al 1986) and positively correlated with the delayed onset of Alzheimer’s disease (AD) (van Duijn and Hofman 1991) have encouraged studies investigating the neuroprotective role of nicotine (e.g., Knott et al 1999; Maggio et al 1998; Perry et al 1996; Ulrich et al 1997). So far, in vivo studieshave been inconclusive (Behmand and Harik 1992; Janson and Møller 1993), but in vitro evidence has demonstrated more convincingly that nicotine inhibits cell loss induced by excitotoxic agents (Akaike et al 1994; Marin et al 1994).
Nicotinic receptor binding and choline acetyltransferase are positively correlated with smoking (Parks et al 1996). In this respect, it is pertinent that AD has long been associated with a cholinergic deficit, characterized by marked degeneration of cholinergic innervation from the nucleus basalis of Meynert to the cerebral cortex (Candy et al 1983), reduced levels of choline acetyltransferase and acetyl cholinesterase, and a much decreased density of nicotinic and M2 muscarinic receptors in the cerebral
cortex and hippocampus (Davies and Maloney 1976; Flynn and Mash 1986; London et al 1989; for a review, see Roßner et al 1998). In this review aspects of the nicotinic acetylcholine system,b-amyloid protein (bAP) neurotox-icity, and the protective role of nicotine against bAP toxicity are presented.
Nicotinic Acetylcholine Receptors
Nicotinic acetylcholine receptors (nAChRs) are ligand-gated calcium-permeable receptors consisting of at least eight a-like subunit isoforms (a2–a9) and three b-like isoforms (b2–b4) (Kim et al 1997). These subunits, either as homomeric (a7–a9) or heteromeric (requiring b sub-units), form receptors with distinct spatial and tissue-specific distributions (McGehee and Role 1995; Zarei et al 1999). In the neocortex the predominant subtype isa4b2, whereas others containa4 anda3. The hippocampus, on the other hand, is rich ina7 subunits that could form the homomeric receptor (Wonnacott 1997). g-Aminobutyric acid (GABA)– ergic interneurons in the hippocampus possess nAChRs the activation of which leads to an increase in GABA release (Alkondon et al 1997; Lena and Changeux 1997; McMahon et al 1994; Radcliffe and Dani 1998). Enhanced GABA release by nicotine has been extensively studied at various drug concentrations (low
mmol/L range equivalent to smokers’ intake and higher
mmol/L range similar to synaptic cleft concentrations), and in all cases nicotine increases the release of the inhibitory
From School of Biosciences, Cardiff University, Cardiff (MRZ) and the Depart-ment of Human Anatomy and Cell Biology, The University of Liverpool, Liverpool (YSA), United Kingdom.
Address reprint requests to M. Reza Zamani, Cardiff University, School of Biosciences, PO Box 911, Cardiff CF10 3US, Wales, United Kingdom. Received June 1, 2000; revised November 14, 2000; accepted November 28, 2000.
neurotransmitter (Radcliffe et al 1999). Recently it has been shown that these cholinergic receptors desensitize in response to nicotine when exposed with a time course and concentration equivalent to smokers’ intake, thereby re-ducing GABA release (Fisher et al 1998).
Relative to nonneuronal tissues, neuronal AChRs and the a7 receptor have higher Ca21 permeability to the extent that calcium influx through these channels at presynaptic terminals may cause transmitter release (Cas-tro and Albuquerque 1995; Decker and Dani 1990; Pugh and Berg 1994; Radcliffe et al 1999; Seguela et al 1993; Vernino et al 1992, 1994).
Physiologically, nAChRs are distributed at presynaptic (terminal), postsynaptic (dendrites), and somatic sites (Wonnacott 1997). In the hippocampus, presynaptic acti-vation of nAChRs is thought to dominate over the postsyn-aptic activation, which enhances neurotransmitter release at excitatory, inhibitory, and modulatory synapses (Fu et al 1999; Radcliffe et al 1999; Vidal 1996; Wonnacott 1997). For example, glutamatergic synapses containa7 receptors, which respond to nicotine resulting in an increase in the frequency of miniature excitatory postsynaptic currents in a tetrodotoxin (TTX)-independent manner suggesting a presynaptic location (Araujo et al 1988; Gray et al 1996; McGehee and Role 1995; Sacaan et al 1996). In studying the nAChR system in both the cortex and hippocampus, nicotine is seen to regulate its own release, implying the existence of self-reinforcing autoreceptors (Araujo et al 1988; Rowell and Winkler 1984; Wilkie et al 1996; for a review, see Wonnacott 1997). Furthermore, the rate of expression and distribution of nAChR subunits changes during development (Broide et al 1995; Court et al 1997; Zarei et al 1999; Zhang et al 1998) and in humans during aging (Marutle et al 1998).
The complexity of the nicotinic acetylcholine system underlines the importance of therapeutic strategies target-ing specific brain regions and/or receptor subtypes. Below, how the neuronal cholinergic system is affected in AD is considered briefly.
Cholinergic System and Alzheimer’s Disease
Deficit or mutation in the cholinergic neurotransmission system is seen in a number of neurologic disorders, but in AD, the cholinergic system is believed to be the primary target (Bowen et al 1976; Davies and Maloney 1976; Perry et al 1977). This does not preclude the involvement of other neurotransmission systems, and in fact, since the report by Davies and Maloney (1976), other neurotrans-mitter systems have shown either functional deficit in different brain regions or differential downregulation of their receptor subtypes (for a review, see Kanfer et al 1999). Chronologically, cholinergic deficit in AD
pre-cedes the deficit in other neurotransmitter systems. This has led to the conclusion that the deficit in other neuro-transmitter systems may be the consequence of cholinergic denervation reflecting transynaptic function of this system (Kanfer et al 1999).
The role of nAChRs in cognitive function and develop-ment is well docudevelop-mented (e.g., Granon et al 1995; Levin 1992; Meyer et al 1998). The loss of cognitive perfor-mance in AD and Parkinson’s disease patients is positively correlated with the degree of central cholinergic deaffer-entation (Flynn and Mash 1986; Perry et al 1987a, 1987b; Rinne et al 1991; Sugaya et al 1990; for a review, see Roßner et al 1998). Furthermore, nicotine “replacement” reduces cognitive deficit and improves short-term, visual, and semantic memory in these patients and in animal models of AD (Hodges et al 1991a, 1991b; Jones et al 1992; McGurk et al 1991; Newhouse et al 1990; Perry et al 1996; Voytko et al 1994; for a review, see Vidal 1996). To identify changes in nAChR subtypes, Martin-Ruiz et al (1999) studied AD brain tissues after autopsy and found a significant reduction ina4 receptor subunits but nota7 ora3 ones as compared with age-matched samples. The same subtype (a4) showed a significant binding elevation in a subgroup of control individuals who were habitual smokers. Similar findings are reported by Sugaya et al (1990) (see also Schroder and Wevers 1998). Although these results agree with others (Perry et al 1995) showing a significant drop ina4 –b2 subunits, a greater loss ofa7 subunits is seen in the midtemporal gyrus (but not in the frontal cortex or hippocampus) of the AD brain (Davies and Feisullin 1981; Sugaya et al 1990; Warpman and Nordberg 1995). Also, significant reduction ina3 anda4 subunit binding from AD brains with Swedish mutation is seen (Marutle et al 1999). Moreover, immunocytochemi-cal studies on postmortem AD brains have revealed significant reduction ina3 anda4 subunits in the temporal cortex and, in addition to these subunits, a significant reduction in a7 subunit in the hippocampus (Guan et al 2000). It should be noted that, in contrast with the above reports, no changes in message expression fora3 anda4 are seen (Hellstrom-Lindahl et al 1999; Terzano et al 1998). In fact, an increase in the level of a7 messenger RNA (mRNA) is reported by Hellstrom-Lindahl et al (1999). Although variation in techniques and subject selection might be a factor in the apparent lack of concordance in these reports, they clearly signify changes in posttranscriptional stages of the nicotinic system in AD.
b
AP Is Neurotoxic
sites of action, is closely linked to AD (for details, see Roßner et al 1998).b-Amyloid protein is a major constit-uent of senile plaque, a neuropathologic hallmark of AD, and has been shown to be neurotoxic both in vivo and in vitro. A shorter, hydrophobic fragment of the protein,bAP (25–35), though not present in biological systems, is widely used together with, or instead of, the endogenous fragment (bAP (1– 42/43)) by a number of investigators and is found to be at least as toxic as the full-length fragment (Yankner et al 1989).
In a series of experiments bAP (25–35) (0.01 to 100
mmol/L, 5 days), given to 1-week-old hippocampal neu-ronal cultures, caused toxicity in a dose-dependent manner (Zamani et al 1997). The percentage of cells surviving was reduced from 8567% to 2964% at 0.1mmol/L to 100
mmol/LbAP concentrations, respectively. The scramble fragment of the peptide did not induce neuronal loss. Kihara et al (1997) also saw some 60% cell loss with 20
mmol/LbAP (25–35) after a shorter, 48-hour incubation period. However, since their results show a linear time-dependent toxicity effect, more cell loss would be ex-pected after 48 hours of incubation.
Both bAP (1– 42) and (25–35) peptides aggregate in solution at different rates, with the former requiring some 24 hours for aggregation and the latter a few hours (Pike et al 1995). Both fragments, whether fresh (diffusible, nonfibrilar form) or “aged,” however, show neurotoxic effects (Pike et al 1993; Terzi et al 1994, 1997).
bAP Modification of Ion Channels
To study the mechanism of bAP neurotoxicity, several laboratories have looked at immediate to late physiologic events following exposure of neurons or neuronlike cells to various forms ofbAP fragments. One early physiologic action of bAP is an increase in intracellular calcium concentration ([Ca21]). In nerve growth factor–treated PC12 cells, the increase in [Ca21] is immediate and dose
dependent, which suggests a membrane effect (Joseph and Han 1992). Similarly, some doubling of [Ca21] is reported in hippocampal primary cultures 24 hours after exposure to agedbAP (25–35) (Mattson et al 1993b; Mogensen et al 1998).
HowbAP fragments induce increased [Ca21] has been the subject of several studies. The early events seem to involve integration of these peptides with the membrane. In fact, using artificial membranes Terzi et al (1994) and Terzi et al (1997) found that both short and long frag-ments—bAP (25–35) and bAP (1-42), respectively— have a tendency to insert themselves into liposomes. Moreover, using the whole-cell patch clamp technique, Sanderson et al (1997) found that aggregatedbAP (25–35) exerts its disruption of calcium homeostasis by forming
membrane ionophores permeable to calcium. In support of channel formation, Arispe et al (1994a) suggest that the conductance is large enough to disrupt calcium homeosta-sis and possibly cause cell death in vivo.
Reports from other laboratories suggest an additional role for the bAP mechanism. Thus, bAP is found to enhance the activity of ligand-gated calcium channels or voltage-dependent calcium channels (VDCCs), with little or no effects on calcium homeostasis by itself. In the NIE-115 cell line, nimodipine (L-type channel selective) blocked the calcium current due tobAP (Davidson et al 1994). However, at the 100mmol/L concentration used in their study, nimodipine could also have blocked N-type channels. Further support for the involvement of L-type VDCCs comes from Ueda et al (1997), who succeeded in preventingbAP (25–35) effect with L-type blockers, but not with blockers of N and P/Q channel. The protective effect of L-type channel blockers was not due to a reduction in free radicals, but to their ability to prevent an increase in [Ca21]. However, the antioxidant vitamin E prevented the production of free radicals and rise in [Ca21] by bAP. It is proposed, therefore, that chronic treatment with bAP may form free radicals, which then increase [Ca21] via activation of VDCCs (Ueda et al
1997). This finding was supported in a study where the process ofbAP (25–35) orbAP (1– 40) toxicity consisted of an early, calcium-insensitive redox phase (0 –12 hours posttreatment) and a late, calcium-sensitive cell death phase (3 days onwards) (Abe and Kimura 1996). This was contrary to glutamate-mediated neuronal loss, where the “early phase” redox period and “late phase” calcium-sensitive lactate dehydrogenase (LDH) production period were almost contemporaneous (Abe and Kimura 1996).
In rat membrane preparation, N-methyl-D-aspartate re-ceptor (NMDAR) involvement is not clear, with some reporting an enhancement and others suggesting a reduc-tion of binding of MK-801, glutamate, or glycine bybAP (Calligaro et al 1993; Cowburn et al 1994, 1997). In hippocampal neuronal cultures, however, Brorson et al (1995) foundbAP (25–35)– or (1– 40)–mediated increase in [Ca21] leading to an increase in spontaneous bursts that were inhibited by TTX, AMPA receptor, NMDAR, or L-type VDCC blockers. But, no direct enhancement of NMDAR- or kainate receptor-mediated calcium influx was observed.
Despite a strong support from a number of groups, the role of VDCCs and glutamatergic receptors in bAP toxicity has not been resolved completely. Whitson and Appel (1995), for example, found no VDCC or NMDAR involvement in their hippocampal neurons exposed to bAP (1– 40). Furthermore, in PC12 cells,
sensi-tive to antioxidants such as vitamin E. This is attributed to the ability ofbAP (25–35) to produce free radicals shortly after its preparation in solution (Hensley et al 1994). It is noteworthy that the elevated free radical formation has been reported in postmortem tissues from AD patients (Zhou et al 1995).
An intracellular signal for the release of neurotransmitters is indicated by an increase in presynaptic Ca21. It would therefore be expected thatbAP should enhance neurotrans-mitter release. This was the case in both young and aged rats, for excitatory but not inhibitory neurotransmitters under K1-induced depolarization in vitro (Arias et al 1995).
How-ever, if this is followed by depolarization mediated by high K1concentration, then the neurotoxicity is prevented (Pike et al 1996). This phenomenon is attributed to the depolariza-tion-mediated activation of VDCCs, since pretreatment with a VDCC activator, bay-K, under a “mild” depolarization (10 mmol/L K1), was also found to be protective againstbAP
toxicity (Pike et al 1996).
In addition to calcium channel activity, bAP seems to require active K1channels. For instance, tetraethylammoni-um-sensitive delayed-rectifier K1channels were involved in thebAP (1– 40)-mediated neurotoxicity in the septal/neuro-blastoma hybrid cell line SN56 (Colom et al 1998). The sister hybrid cell line, SN48, devoid of tetraethylammonium-sen-sitive K1channels, resistedbAP (1– 40) neurotoxicity. No-ticeably, SN56 cells do not seem to express high threshold calcium channels and possess low threshold Ni21-sensitive calcium channels instead that are not involved inbAP (1– 40) neurotoxicity (Colom et al 1998). The mechanism for this increased K1current bybAP and ensuing neurotoxicity is
unknown, but oxidative stress may be a factor (Colom et al 1998). The protective effect of tetraethylammonium is seen as its ability to raise [Ca21], which is mimicked by increased depolarization induced by high extracellular K1 concentra-tion ]K1[. And as seen above, high ]K1[ significantly protects againstbAP assault in hippocampal neurons (Pike et al 1996).
The above reports suggest that bAP exerts its neuro-toxic effect via different routes, which are probably tissue or cell type specific and occur at various developmental stages. In support of this notion, Scorziello et al (1996) show thatbAP (25–35) causes significantly more neural toxicity in immature cerebellar granule cell cultures but only slightly enhanced glutamate-mediated cell loss in mature (differentiated) cultures.bAP (25–35) alone does not affect the basal levels of [Ca21] but enhances
gluta-mate-mediated neurotoxicity. This b-amyloid-enhanced neurotoxicity is not mediated by NMDAR activity, sug-gesting a different route for Ca21 influx (Scorziello et al 1996). Furthermore, due to its high inhibitory physiology, cerebellar tissue shows a distinctly different response to
bAP neurotoxicity. According to Price et al (1998),
cerebellar granule neurons show an increasedb AP-medi-ated [Ca21] rise through mainly N-type and not L-type
calcium channels. No nonspecific ionophore formation, due tobAP integration with the membrane, was observed in their study. Recently, we also found some cell type specificity forbAP (25–35) toxicity. In young organotypic hippocampal slices,bAP was found to be toxic both to dentate gyrus granule cells and CA1/CA3 pyramidal cells. However, in 6-month-old slices neuronal loss was mainly confined to the pyramidal cell layer (Y.S. Allen and M.R. Zamani, unpublished data) (Figure 1). These observations point to possible developmentally regulated mechanisms that render pyramidal neurons more vulnerable to bAP toxicity than granule cells.
In summary, it is evident thatbAP is neurotoxic, but its mode of action may vary depending on several factors. These may be summarized as 1) neuronal cell types (e.g., hippocampal vs. cerebellar), 2) uniformity of culture (whether or not cultures contain glial “scaf-folding”), 3) type of culture (acute brain slice, dissoci-ated culture), 4) developmental stage of the culture (mature vs. immature, differentiated vs. undifferenti-ated), 5) age of the animal from which the cultures or brain slices are obtained (embryonic, postnatal, adult), 6) density of cultured cells (Mattson et al 1993a), 7) the
b-amyloid fragment type (25–35 vs. 1– 40) (Kihara et al 1997, 1998), 8) “age” and concentration of the fragment (Mattson et al 1993a), and 9) duration of exposure of cells to thebAP fragments.
Cellular Events following Ca21Mobilization
Since the accumulation ofbAP in the brain is gradual and progressive, the induction of neuronal death should take a
more “physiologic” course rather than the large and sudden rises in [Ca21] seen in most in vitro preparations. Specific signal transduction cascades may become in-volved during bAP accumulation in the affected brain, which compromise cell membrane integrity by reconfig-uring membrane-associated proteins, modulate the activity of cation channels, cause conformational changes in pro-teins, induce protein turnover, and eventually cause cell death.
Support for the above scenarios is accumulating. For example, long-term modification of VDCCs bybAP may be sensitive to functional metabotropic glutamate recep-tors (mGluRs). According to Copani et al (1995), mGluR agonists preventedbAP (2–35)-mediated cell loss in both cerebellar granule cells and mixed cortical cultures. Their results were consistent with the use of agonists for specific mGluR subtypes for different cultures, since cerebellar granule cells express mGluR subtypes in different propor-tions than cortical cultures (Tanabe et al 1992). The data are interpreted in terms of VDCC inhibition mediated by mGluR activation. Consistent with this interpretation, Copani et al (1995) found that direct inhibition of VDCCs was as “neuroprotective” against bAP toxicity. No G-protein analysis was done in this work, but Sorrentino et al (1996) and Singh et al (1997) support the notion of a pertussis toxin-sensitive bAP-mediated signal transduc-tion pathway.
Ekinci et al (1999), on the other hand, support the notion of protein modification bybAP. They found that
bAP imposes neurotoxicity by increasing tau phosphory-lation. Tau is the major component of neurofibrillary tangles in the brains of AD patients. Abnormal phosphory-lation of tau can lead to the formation of paired helical filaments of the neurofibrillary tangles. It has therefore been suggested thatbAP-mediated tau phosphorylation is achieved through activation of the mitogen-activated pro-tein signal transduction pathway leading to phosphoryla-tion of L-type calcium channels with a consequence of increased VDCC activity and [Ca21] elevation. This
triggers calcium-dependent kinases such as protein kinase C and calcium-calmodulin-dependent kinase that phos-phorylate tau (Ekinci et al 1999).
Activation of transduction pathways can lead to in-creased genomic activity and protein turnover. Thus,bAP is shown to induce cycloheximide-sensitive protein syn-thesis (Pike et al 1996).
The end point of bAP-induced toxicity is cell death through necrosis and/or apoptosis. In vitro, this seems to depend on the excitation state of the neural cultures. Thus, concomitant with elevated neural excitation, membrane fragmentation and somatic swelling leading to LDH re-lease ensues (Koh et al 1990; Mattson et al 1992). However, in the absence of elevated neural excitation,
bAP seems to cause an apoptosis-path neuronal death (Forloni et al 1993; Loo et al 1993).
Finally, at low concentrations, early in the course of its synthesis,bAP may have a different biological function than later on when its local concentration in the affected brain is high. Thus, at low (nanomolar or picomolar) concentrations where no direct cell death can be detected in vitro,bAP disrupts cholinergic system by 1) reducing the concentration, release, or synthesis of acetylcholine and 2) reducing choline acetyltransferase and the activity of pyruvate dehydroxygenase (involved in the production of acetylcholine) (Auld et al 1998; Hoshi et al 1997; Kar et al 1996; Roßner et al 1998). If AD in general andbAP in specific compromise the cholinergic system, interven-tion techniques such as “replacement” of cholinergic nuclei or raising the brain’s cholinergic “output” through pharmacologic means may help to alleviate some of the symptoms of the disease.
The Role of Nicotine against
b
AP Toxicity
Recently, several laboratories have addressed the inter-action between bAP and the cholinergic system (Cheung et al 1993; Itoh et al 1996; Kihara et al 1997, 1998; Kim et al 1997; Maurice et al 1996; Monteggia et al 1994; Singh et al 1998a, 1998b; Zamani et al 1997). In most cases bAP-induced toxicity can be signifi-cantly, or even completely, prevented by activating the nicotinic system.
In our hands (Zamani et al 1997), toxicity mediated by
bAP (25–35) (100 mmol/L, 5 days) was partially, but significantly, prevented in hippocampal neurons by nico-tine in a dose-dependent manner and with maximum inhibition at 10mmol/L (Figure 2). The degree of protec-tion was significantly larger when samples were pre-exposed to nicotine for 5 days (chronic) rather than 15 min (acute). At all concentrations, the protective effect of nicotine differed significantly between the two pretreat-ment time courses.
The protective effect of nicotine was receptor medi-ated. Thus, we showed that coadministration of mecamylamine (0.1–10 mmol/L) and nicotine (10
mmol/L) to hippocampal cultures for 5 days signifi-cantly diminished the neuroprotection by nicotine (Fig-ure 2). Mecamylamine (10 mmol/L, 5 days) pretreat-ment alone did not affect neuronal viability or prevent
Thus, simultaneous application of dihydro-b -erythroi-dine, which targets the a4 –b2 nicotinic receptor, pre-vented the protective effect of nicotine. Cytisine, a specific agonist of the a4 –b2 receptor, however, showed a dose-dependent neuroprotective effect. In contrast, some studies have shown protective effects against bAP toxicity with ana7 nAChR partial agonist [3-(2,4-dimethoxybenzylidene)anabaseine] in human cell lines (Meyer et al 1998). In the same way as with Kihara et al (1998), the partial agonist in this study was added simultaneously with bAP (25–35). The apparent discrepancy in these reports is most likely the result of tissue specificity in terms of nAChR subtype distribu-tion and funcdistribu-tion, but the underlying biological path-ways involved in nicotinic protection could be very similar. This point is further elucidated when one compares the protective role of nicotine with other neurotoxins such as glutamate. Here, Minana et al (1998) proposed an a7-sensitive path for glutamate- or NMDA-mediated toxicity, as opposed to an a4 –b 2-mediated path for bAP, as found by others (Abe and Kimura 1996; Kihara et al 1998) and by us (M.R. Zamani and Y.S. Allen, unpublished data).
The “chronic” exposure of neurons to nicotine in our
study (Zamani et al 1997) was an attempt to mimic the condition where nicotine intake through cigarette smoking may precede the onset of AD by many years. The lack of protection against bAP toxicity by nicotine after acute exposure was significant and contrasted with studies where concomitant application of the amyloid fragments and nicotine resulted in significant protection (Kihara et al 1997, 1998). Explanations for this discrepancy may be found in bAP concentrations, its “aging” state, and the length of exposure of neurons to the amyloid fragment. Aggregation ofbAP is not an issue because the solutions were made several hours before treatment, during which aggregation would have occurred (Pike et al 1995). We therefore anticipated that our experimental regimen would be more detrimental to the neurons than the protocol used by others (e.g., Kihara et al 1997, 1998) and that our results pointed to nicotine-induced long-term cellular events, possibly involving genomic activation, that ren-dered neurons resistant to bAP toxicity.
In addition to the in vitro studies, many experiments have been carried out in intact animals to demonstrate
bAP toxicity and its prevention by nicotine treatment. For example, rodents infused cerebrally with either fresh or aged bAP (25–35 or 1– 40) show significantly reduced acetylcholine and dopamine release, and choline acetyl-transferase activity (Itoh et al 1996; Maurice et al 1996). Cognitive functions were also impaired. However, if mice are treated with nicotine or the cholinesterase inhibitor tacrine, thebAP effect is no longer detected (Maurice et al 1996; Nitta et al 1994).
Although convincing evidence by us and others (Kihara et al 1997, 1998) demonstrates the involvement of nAChRs in nicotine-mediated protection, data from sev-eral laboratories suggest a more direct role for nicotine that bypasses its putative receptors. For instance, Singh et al (1998a, 1998b) show that nicotine prevents the activa-tion bybAP (25–35) of phospholipase A2and
phospho-lipase D, but not phosphophospho-lipase C. This may occur through an “atypical” acetylcholine pathway, which is not sensitive to known nAChR antagonists such as hexamethonium and D-tubocurarine. This is similar to data published by Marin et al (1997) involving elevation of phospholipase A2
activity by excitatory amino acids. The nicotine inhibition of bAP toxicity is not likely to be due to the ability of nicotine to prevent aggregation of the peptide (Salomon et al 1996), since in similar preparations nicotine failed to affectbAP-induced elevation in phospholipase C activity (Singh et al 1998b).
Although the exact mechanism of nicotine protection againstbAP neurotoxicity is yet to be elucidated, reports examining nicotine and cholinesterase inhibitors point to a variety of biological events. These range from stimulation of neurotransmitter release to production of trophic factors
Figure 2. (Line graph) Nicotine dose response andb-amyloid protein (bAP) (25–35) toxicity at two different pretreatment times. Cultures were pretreated with nicotine (0.01–100mmol/L) for either 15 min or 5 days beforebAP (25–35) (100mmol/L, 5 days) treatment. Significantly more neuroprotection was seen in a 5-day nicotine pretreatment protocol. (Bar graph)
and inhibition ofb-sheet formation. A few scenarios are considered here. Nicotine replenishment of the central nervous system (CNS) may substitute for the downregu-lated cholinergic system of AD patients leading to in-creased neurotransmitter release at cholinergic sites. This should result in improved cognitive functions. Whether this nicotinic replacement results in slowing down of the progression of AD neuropathology is hard to prove, but epidemiologic studies from smokers, who on average show a delayed onset of AD, would support this conclu-sion. However, no evidence suggests that the course of the disease can be reversed by current therapeutic approaches. Nicotine may also induce the production of trophic factors. In support of this view, Pike et al (1996) found a resistance to toxicity bybAP (1– 42) and (25–35) in hippocampal cultures that were pretreated with depolarizing concentrations of K1. This process was dependent on VDCC activity and protein synthesis. Pre-exposure to high K1 concentrations may trigger synthesis of certain proteins in neurons that render them resistant tobAP toxicity (Pike et al 1996). Similarly, cells more prone to bAP toxicity, when cultured at low density, were rescued by basic fibroblast growth factor pretreatment (Mattson et al 1993b).
Our data (Zamani et al 1997) and those of others suggest that inhibition ofb-sheet formation by nicotine (as reported by Salomon et al 1996) does not play a major role in neuroprotection, since chronic nicotine pretreatment significantly prevented bAP toxicity, whereas concomi-tant exposure withbAP did not. Nicotinic receptor mod-ulation and/or trophic factor production may play a more significant role in this process.
Finally, recent data suggest that nicotine could protect againstbAP by inducing the release of secreted forms of
bAPP. This has been shown by Kim et al (1997) to occur in PC12 cells without affecting APP mRNA expression. The secretedbAPP, produced bya-secretase, is known to have neurotrophic effects and regulate [Ca21] levels (Mattson et al 1993b). The release of secretedbAPP is induced by nicotine and requires functional nAChRs. Furthermore, these soluble fragments can activate fast inactivating K1 channels (Fu-rukawa et al 1996). Nicotine may, therefore, use the same amyloid protein processing machinery to induce a reduction in neural excitation, which then counters the toxic effects of
bAP. Whether nicotine can modulate neurotransmitter re-lease in the CNS of smokers in a similar manner or whether comparable mechanisms are responsible for neuroprotection against bAP and possibly in the late onset of AD and Parkinson’s disease is yet uncertain.
Summary
The pathogenesis of AD involves abnormal production or processing of bAP, especially since Down’s syndrome
(trisomy 21) invariably results in AD (the gene for APP is located on chromosome 21) (Kola and Hertzog 1997). Alzheimer’s disease is also associated with impairment of the cholinergic system, particularly the nicotinic compo-nent, with a loss of acetylcholinesterase and choline acetyltransferase. Early findings by Bowen et al (1976), Davies and Maloney (1976), and Perry et al (1977) have yielded much research. However, in this brief review attention was focused on the neural nicotinic system,bAP toxicity, and nicotine “replacement” for protection against
bAP toxicity.
HowbAP production and its gradual deposition lead to neuronal loss is not fully understood, but growing evi-dence supports the following model:
1. b-Amyloid protein membrane insertion destabilizes the membrane, affecting its fluidity (Avdulov et al 1997; Muller et al 1995; for a review, see Kanfer et al 1999).
2. There is an increase in [Ca21] (Mogensen et al 1998) through either production of cation iono-phores or activation of ligand-gated calcium chan-nels and/or VDCCs, directly, or through G protein-sensitive signals (Arispe et al 1994b; Sanderson et al 1997).
3. Calcium-sensitive cascades are then triggered, lead-ing to enhanced transmitter release, increased tau protein phosphorylation resulting in formation of neurofibrillary tangles, and protein turnover. 4. Neuronal death ensues either by apoptosis or
necro-sis of primarily the cholinergic system.
acetylcholinester-ase inhibitors, resulting in adverse effects such as receptor downregulation or desensitization in areas of the brain unaffected by AD (however, for an alternative suggestion, see Abdallah and el-Fakahany 1991).
To minimize the undesirable side effects associated with nonspecific drugs, recent developments have resulted in the production of pharmacologically more selective cholinergic drugs. An example of such a drug specifically targeting a7 nicotinic receptor subtypes is the partial agonist 3-(2,4-dimethoxybenzylidene)anabaseine, which is currently in clinical trails (Meyer et al 1998) and is shown to have positive therapeutic effects.
An alternative approach for the elevation of cholinergic output in the brain of AD patients is the use of cholines-terase inhibitors. Noticeably, their effect is indiscriminate, resulting in enhanced excitatory, inhibitory, modulatory, or even acetylcholine release at presynaptic sites where nicotinic receptors are found but may be relatively spared by AD. However, if the “soup theory of the brain” is to be favored (Sivilotti and Colquhoun 1995), minimal side effects would be expected.
Cholinesterase inhibitors (some reversible and some irreversible) such as tacrine, donepezil, physostigmine, eptastigmine, metrifonate, rivastigmine, and galantamine have now been used in several studies in patients with Alzheimer-type syndrome and have generally resulted in some improvement, sometimes lasting several years (Eagger et al 1991; Krall et al 1999; Nordberg 1993; Nordberg and Svensson 1998; Summers et al 1986). However, a degree of “habituation” to some of these drugs is apparent.
In summary, drugs targeting specific nicotinic (or mus-carinic) subtypes with preferential central activity will be of future interest, but the cholinesterase inhibitors may still prove to be the most promising in alleviating symp-toms of AD.
The authors thank The Wellcome Trust for financially supporting this work, and very much appreciate the intellectual involvement of Professor Jeffery Gray in the initial stages of this project.
Aspects of this work were presented at the symposium “Nicotine Mechanisms in Alzheimer’s Disease,” March 16 –19, 2000, Fajardo, Puerto Rico. The conference was sponsored by the Society of Biological Psychiatry through an unrestricted educational grant provided by Janssen Pharmaceutica LP.
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