and Alzheimer's disease? - IOS Press

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Journal of Alzheimer’s Disease 8 (2005) 155–160 IOS Press

Is zinc the link between compromises of brain perfusion (excitotoxicity) and Alzheimer’s disease? Christopher J. Frederickson a, Math P. Cuajungco b and Cathleen J. Frederickson a,∗ a

NeuroBioTex, Inc. & The University of Texas Medical School, Galveston TX 77550, USA Harvard Medical School, Department of Otology and Laryngologist, and Massachusetts Eye and Ear Infirmary, Eaton-Peabody Lab, 243 Charles Street, Boston MA 02114, USA

b

Abstract. Prior brain injury is a major risk factor in the development of Alzheimer’s disease. This is true for traumatic brain injury, stroke or ischemic brain injury, and (more speculatively) for brain injury resulting from the hypo-perfusion-reperfusion in cardiac arrest or cardiac bypass surgery and even hypo- or hypertension. Here we propose that the release of excess, toxic, “floods” of free zinc into the brain that occurs during and after all excitotoxic brain injury is a key factor that sets the stage for the later development of Alzheimer’s disease. Rapid and aggressive administration of zinc buffering compounds to patients suffering brain injury may therefore not only ameliorate the acute injury but might also reduce the risk of subsequent development of Alzheimer’s disease.

1. Introduction In the present paper we propose that the link between brain injury and the later development of Alzheimer’s disease may be mediated by a release of zinc that is triggered by brain injury and causes, in turn, the seeds of Alzheimer’s pathology to be planted. The “seeds” are the Zn:beta-amyloid deposits that precipitate during and after the brain injury. The hypothesis rests on the following set of causal relationships, for which we marshal evidence in later sections of this review (Fig. 1). The relationships are as follows: 1. Prior brain injury is a risk factor for later development of Alzheimer’s disease. 2. The elevated risk is true for any type of brain insult that involves compromise of brain blood flow, including traumatic brain injury, stroke, ischemia, cardiac arrest, coronary by-pass surgery and, most speculatively, even undergoing general anesthesia, and those with impaired brain perfu∗ Corresponding

author. E-mail: [email protected].

3.

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5.

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sion due to atherosclerosis or high and low blood pressure. All of the brain injuries described above induce the so-called “excitotoxic” cascade, in which, among other events, there is “flood” of excess free zinc released into the extracellular fluid of the brain. The availability of an elevated concentration of free (exchangeable) zinc promotes precipitation of soluble amyloid into insoluble beta amyloid deposits, the core ingredient of the hallmark senile plaques of Alzheimer’s disease. Amyloid deposits precipitated by zinc in a brain that is otherwise, young, healthy, and endowed with “good” amyloid processing genes will likely be resorbed over time without further consequences. In animals or patients that are old, and/or lacking “good” genes for amyloid-processing enzymes, the “pre-plaques” deposited by excitotoxic zinc release can persist, collecting more zinc, amyloid, and copper thereby stimulating the gradual, inexorable development of Alzheimer’s disease.

ISSN 1387-2877/05/$17.00 © 2005 – IOS Press and the authors. All rights reserved

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C.J. Frederickson et al. / Is zinc the link between compromises of brain perfusion (excitotoxicity) and Alzheimer’s disease?

1

1 3

1 2

amyloid Zn MT3

1

NO Depol

Fig. 1. Whenever the brain suffers hypoperfusion-reperfusion injury, the excitotoxic cascade involving release of glutamate, generation of nitric oxide (NO) and depolarization of neurons (Depol) is triggered. These initial events “1” lead to the release of free zinc (Zn) both from the zinc-containing synaptic terminals and from the metallothionein-3 (MT3) protein in the neurons. Those secondary events “2” lead to the precipitation of soluble amyloid into plaque with “3”, the plaque either enduring to promote subsequent Alzheimer’s pathology, or being resorbed, depending on the age, health, and genetic endowment of the brain.

2. The evidence 2.1. Free zinc signals in the brain Zinc signaling is a relatively new phenomenon in neuroscience, which has become recognized as important in both the normal function and pathological function of the brain [31,78]. From data accumulating in the last two decades, it has become clear that brain cells release into the extracellular fluids “signals” consisting of surges or “puffs” of free zinc [48,84,88]. There are at least two types of these zinc signals. First, about half of the glutamatergic presynaptic terminals in the cerebral cortex, contain zinc, along with glutamate, in their secretory presynaptic vesicles [64,76]. This synaptically-stored zinc is released, along with glutamate, whenever those neurons are physiologically active. The synaptically-released zinc apparently acts primarily to down-regulate the NMDA-type glutamate receptors [60]. Second, it has now become clear that once neurons are placed in oxidative or nitrosative stress, free zinc is released into the cytosol of those neurons [4,29,32]. One major source of that zinc is the protein thionein-3, a brain-specific protein which, when fully zincated, is known as metallothoionein-3 (MT-3) [52–54]. Nitric oxide, in particular, is a potent releaser of zinc from MT 3, because the thiol ligands of MT3 are readily nitrosylated, releasing up to seven atoms of zinc per MT3 molecule [42,97]. Like synaptically released zinc, the zinc that mobilizes from within cells can rapidly move into the extra-

cellular space, thereby gaining entry into neighboring cells and access to extracellular zinc sensitive sites on those cells [90]. These movements of zinc are presumed to progress via zinc-permeable channels and zinc transporters, running in either direction, depending on the direction of zinc gradients [3,14,15]. 2.2. Are the excitotoxic brain injuries risk Factors for Alzheimer’s? Traumatic brain injury is well-established as a risk factor for Alzheimer’s disease [39]. In 1995, Rasmusson et al. reported that head trauma may be a predisposing factor for AD. More evidence has recently confirmed this observation in humans and in the AD transgenic mouse model [27,37,40,41,51,57,65,72]. In a recent human study of severely head-injured patients, it was observed that Aβ42 and two soluble forms of its precursor protein (AβPP) were markedly increased in the ventricular cerebrospinal fluid [59]. Marked elevation of AβPP and Aβ expression levels are also found at the sites of pathology following traumatic brain injury [2,96]. In addition to traumatic brain injury, injuries that disrupt the blood flow to the brain also increase the later risk of developing Alzheimer’s. Specifically, although there are some conflicting reports, there is substantial data to indicate that prior stroke is a significant risk factor for Alzheimer’s disease [21,28,34,62,77]. Another example is the disturbance of blood flow through the brain that accompanies coronary artery by pass surgery. It is established that such by pass surgery


can lead to cognitive losses, although the new “beating heart” surgical methods reduce this cognitive deficit, presumably by reducing the hypoperfusion-reperfusion events. Both the beating heart procedure and the conventional by-pass procedures also elevate the risk of subsequent Alzheimer’s disease [71,80], Cardiac arrest also leads to events indicative of early Alzheimer’s plaque formation [66–68,94]. Finally, there is evidence that either hypertension or hypotension can increase the risk of Alzheimer’s disease [62,63,89], and it is easy to imagine how both of those conditions would result in episodes of micro-hypo-perfusion reperfusion episodes in patients. Atherosclerosis, especially confirmed sclerotic plaques in major brain arteries is another risk factor [70], which, again, is easy to identify with crises of cerebral hypoperfusion, as is the use of inhaled general anesthetics [26]. In a review advancing the notion that vascular factors compromising cerebral perfusion may be the main cause of Alzheimer’s disease, de la Torre lists over a dozen prefusion-related risk factors for Alzheimer’s [22,23]. 2.3. Zinc release in excitotoxic brain injury Although zinc signaling appears to be a integral part of normal brain function [20,56], their also occurs in brain injury an exaggerated form of this zinc signaling. What have come to be called “floods” of free zinc are released into the brain during and after various types of brain injury [30,32,81]. The concentration of such “floods” of released zinc in the extracellular fluids has been measured as high as 10–30 µM in brain slug experiments [48,90,91], and as high as several hundred nM by microdialysis in vivo [32]; Frederickson et al. [31]. Other data show that high nanomolar (RB Thompson personal communication) to low micromolar concentrations of free zinc are cytotoxic [10,11] . 2.4. Does zinc speed the AD process In 1997, Cuajungco and Lees hypothesized that spatial and temporal variations of pathological brain zinc levels contribute to disease progression in AD as a consequence of initial floods of zinc that potentially precipitate Aβ and contribute synergistically to neurotoxicity [17]. Nitric oxide (NO) as mentioned earlier, plays a major role in pathological zinc trans-mobilization in neurons [18,29]. NO has been implicated as a crucial contributor to excitotoxic brain insults like that seen in TBI [12,13,55]. Zinc, amyloid accumulation and NO

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appear to be intertwined at the molecular level with regard to the relative risk for AD in TBI. A case in point, intra-cerebral injection of Aβ25-35 or Aβ42 in rat CNS enhances expression of inducible or neuronal nitric oxide [58]. Furthermore, postmortem examinations of AD brain tissues indicate that peroxynitrite (ONOO), a by-product of NO, might be involved in the etiology of AD [45,46,61,79,95];. On the other hand, postmortem studies of AD brain show zinc elevation in various CNS regions, especially those mostly affected by AD [19,24, 50,83]. Note also that there exist significant elevations of histochemically labeled metallothionein (MT) I and II isoforms among astrocytes and microcapillaries in postmortem AD brain tissue [1,99]. Since zinc is a potent inducer of MT expression [33,38] this apparent overlap between zinc and MT overexpression is further evidence of the likely pathological effect of high zinc levels in the AD brain. Zinc precipitates Aβ and interacts with AβPP [5, 6,31,35]. Although redox active metals like copper and iron are also implicated in AD, evidence suggest that zinc has a central role in amyloid formation. This observation comes from findings that when transgenic animals knocked out of ZnT-3 (a vesicular zinc transporter in the brain) were crossed with amyloidproducing AβPP2576 transgenic mice, significant reduction of plaque load and insoluble Aβ were found in their progeny’s brains compared to controls [47]. Further evidence that zinc may mediate AD pathology comes from experimental studies using metal chelators [7,16,25,69,85]. One metal chelating agent, clioquinol, holds some promise in an AβPP2576 transgenic mouse model for AD [8]; however, human clinical trial for this chelating drug is still underway [36] and efficacy is yet to be shown.

3. Conclusions and recommendations What was once called “glutamate toxicity,” and “excitotoxicity,” was for several decades attributed to fluxes of calcium flowing into neurons through channels opened by glutamate and/or depolarization [49, 86]. Recent data have emphasized the importance of zinc fluxes through those same channels, rather than calcium fluxes in excitotoxic neuronal injury [9–11, 31,73–75,92,93]. Probably the single-most important finding drawing attention to the pivotal toxic role of zinc is the oft-repeated finding that chelation of zinc (without altering calcium) or other methods of reducing zinc flux is profoundly neuroprotective in both cell and

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animal models of excitotoxicity [43,81,82,87]. Parallel encouraging results are now reported for zinc buffering in the case of human stroke victims [44,98,98,98]. As concerns the parallel role of zinc in Alzheimer’s plaque formation the recent findings of the Koh and Bush groups [47] showing that the ZNT-3 knockout dramatically reduces plaque formation in mutant mice. Because buffering the intracerebral zinc to physiological levels in excitotoxic crises can reduce the acute neuron loss, and because it may also reduce the elevation of the later risk of Alzheimer’s disease as a sequella of the excitotoxicity, such buffering with suitable compounds might well be recommended as the standard of care. Supported in part by NIH Grants NS40215,NS41682, and NS42882 to CJF and CJF.

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