Elsevier

Medical Hypotheses

Volume 84, Issue 5, May 2015, Pages 460-469
Medical Hypotheses

Paradigm shift redefining molecular, metabolic and structural events in Alzheimer’s disease involves a proposed contribution by transition metals. Defined lengthy preclinical stage provides new hope to circumvent advancement of disease- and age-related neurodegeneration

https://doi.org/10.1016/j.mehy.2015.01.044Get rights and content

Abstract

It is estimated that 5.5 Million North Americans suffer from varying degrees of Alzheimer’s disease (AD) and by the year 2050 it may be one in 85 people globally (100 Million). It will be shown that heavy metal toxicity plays a significant role in sporadic AD. Although current literature speaks to involvement of metal ions (via Fenton reaction), studies and reviewers have yet to link cellular events including known structural changes such as amyloid plaque development to this metal toxicity the way it is proposed here.

Contrary to the current AD model which positions BACE1 (β-secretase) as an aberrant or AD-advancing enzyme, it is proposed herein that the neuron’s protective counteraction to this metal toxicity is, in fact, a justified increase in BACE1 activity and amyloid precursor protein (APP) processing to yield more secreted APP (sAPP) and β-amyloid peptide in response to metal toxicity. This new perspective which justifies a functional role for APP, BACE1 enzyme activity and the peptide products from this activity may at first appear to be counterintuitive.

Compelling evidence, however, is presented and a mechanism is shown herein that validate BACE1 recruitment and the resulting β-amyloid protein as strategic countermeasures serving the cell effectively against neuro-impeding disease. It is proposed that β-amyloid peptide chelates and sequesters free heavy metals in the extracellular medium to aggregate as amyloid plaque while unchelated β-amyloid migrates across the cell membrane to chelate intracellular free divalent metals. The sequestered intracellular metal is subsequently chaperoned as a metallo-peptide to cross the plasma membrane and aggregate as amyloid plaques extracellularly. The BACE1 countermeasure is not genetic or metabolic aberration; and this novel conclusion demonstrates that it must not be inhibited as currently targeted. APP, BACE1, β-amyloid peptide, and sAPP play positive roles against the preclinical oxidative load that predates AD symptoms for as long as 20 years.

A healthy neuron may tolerate free metal toxicity, such as iron in the case of injury-induced amyloid, for as long as twenty years due to this very BACE1 activity. In later stages, the uncontrolled metals and ROS are compounded by other factors which together overcome this BACE1/β-amyloid protein countermeasure. This results in a sudden increase in IL-1 leading to Tau’s hyperphosphorylation as cited and eventually to Tau dissociation from the microtubule cytoskeleton interrupting cell trafficking. At this later stage of AD the β-amyloid protein which once served as a vehicle to escort toxic metals to the extracellular medium and a trap to form a relatively benign extraneuronal disposal site is no longer translocated due to interruption of trafficking and now accumulates intracellularly facilitating hyper-oxidative ROS levels and contributes to irreversible neuron apoptosis.

Introduction

It is estimated that 5.5 Million North Americans have Alzheimer’s disease (AD) with the number expected to increase significantly by the year 2050 to one in 85 people globally (100 Million) imposing a huge strain on families, health care logistics and health care costs. Early detection appears to be a critical factor in the circumvention of AD. It is understood and now well accepted that a preclinical stage can begin as long as two decades before AD symptoms are evident. However, the markers that may serve as AD indicators in these early stages may not be easy to differentiate from those produced by healthy brains. The only diagnostic protocol for AD today is detection in changes of amyloid peptide (increased proportion of β-amyloid 40 and 42) fragments and Tau protein in cerebral spinal fluid samples [50], [103]. Despite these markers definitive diagnosis is still only possible with post-mortem evaluation of the brain for signs of accumulated plaques, tangles and neuron loss. Unpublished preliminary research by Pelech, however, points to a less intrusive diagnostic method of serum antibody and other markers in peripheral blood work that may serve as easy detection targets for AD [80]. Such diagnostic tools would serve the preventive initiative outlined in this review and research proposal very well.

As much as there are definitive genetic markers for AD risk such as chromosome 21 amyloid precursor protein (APP) and presenilin gene mutations, to name a few, it is expected that only 5% of AD cases are familial or inherited while the majority are a function of sporadic or idiopathic development [58], [96]. This indicates a significant environment- or lifestyle-associated contribution to the development of both familial and sporadic cases. The preliminary research that has led to the current position in this review indicates that uncontrolled oxidation and downstream inflammation play critical roles in early stages of disease and sets in motion its development. However, propagation of disease by oxidation is not novel thinking. Literature also shows that heavy metals can play a significant role in amyloid deposition in the Alzheimer’s brain [2], [16], and this too is not news. However, the way this metal toxicity and the oxidation it facilitates factors into cellular events related to β-amyloid protein is something that has not been expressed the way it is in this review.

The hallmarks of AD include extracellular amyloid plaque aggregate made up of insoluble β-amyloid protein fibrils and intracellular hyperphosphorylation of Tau which leads to the formation of neurofibrillary tangles (NFTs) [108]. Research points irrefutably to oxidative load and neuroinflammation in the AD brain which present as additional hallmarks of AD. However, unlike the tangible identification of amyloid plaques (AP) and NFTs in post-mortem evaluations, the markers of oxidative load or insufficient endogenous antioxidant saturation are more difficult to pin down.

  • (1)

    Key positioning statement of the hypothesis: It will be shown that the neuron’s protective counteraction to this compounded oxidative stress is, in fact, incremental synthesis of amyloid precursor protein (APP) and the processing yield from this protein, β-amyloid peptide. This perspective may at first appear to be counterintuitive based on currently studied models, however, when we look at the signaling sequence summarized in Fig. 5, the incremental ROS and the NF-kappa-B it induces is shown to induce BACE1. From here it is evident that BACE1 recruitment is inspired as a function of ROS and NF-kappa-B activation and in accordance with the hypothesis is positioned in the sequence as a reaction to oxidation and inflammation – a protective countermeasure. However, the hypothetical role of β-amyloid peptide is far more specific again.

    • It is proposed herein that β-amyloid peptide serves as a chelating agent to sequester toxicity of accumulating intracellular metal ions that facilitate oxidative activity via Fenton reaction. The β-amyloid peptide chelates and traps extracellular toxic divalent metals like copper, iron, lead, mercury and others and forms the notorious plaque. It can translocate auto- or para-directionally to enter the cell where it traps and chaperones the metal ions to the extracellular medium. The metallo-β-amyloid peptide further accumulates as amyloid plaque deposit and in this form and placement does not pose the same immediate danger to the cell. When we consider the facts described herein, it becomes more evident that this BACE1 activity may be a justified cellular design that is intended to protect a cell in distress.

Presenilin mutations are linked to early onset familial AD [48]. Presenilin 1 and presenilin 2 mutations result in the alteration of amyloid β peptide processing from amyloid β precursor protein (APP) [95]. These mutations lead to increased and altered γ-secretase enzyme expression to yield abnormally elevated amounts of the toxic amyloid β peptide [20], [28], [35].

Parkinson’s disease (PD) displays similar characteristics, however, centered on different peptide aberrations. In PD α-synuclein gene mutations can result in a gain-of-function mechanism the outcome of which is an abnormally high cytoplasmic accumulation of α-synuclein forming Lewy bodies [99]. These aggregates can also include ubiquitin and synipilin-1; proteins involved in facilitation of proteasomal degradation [24].

This indicates an attempt by the preclinical PD cell to eliminate the aberrant α-synuclein via ubiquitination and subsequent proteasomal degradation. However, failure of degradation by the proteasome pathway results in the characteristic Lewy body deposits located in the neuron cell bodies, axons and even synapses [47], [90], [95]. Accumulation of the aberrant α-synuclein is thought to contribute to degeneration of dopaminergic neurons [25].

A study using transgenic mouse models of PD overexpressing α-synuclein shows a progressive increase in phosphorylated-Tau similar to that formed in AD [43]. Another study by Lee et al. show the possibility of a mechanistic link between Tau and α-synuclein contributing to the overlap in pathological and clinical features of AD and PD [60].

  • (2)

    Key positioning statement of the hypothesis: In AD it is proposed as a component of the new paradigm that the BACE1 compensatory system functions at designed capacity to counter metal toxicity by chelating the metal with the β-amyloid peptide and disposing of it as the relatively benign extracellular amyloid plaque. In PD, metal toxicity, in particular copper (Cu II) and iron (Fe II) are implicated in the induction of oxidative cross-linking of α-synuclein [9], [11], [46], [53], [101].

    • Furthermore, it is shown that amyloid plaques of AD patients can contain α-synuclein [102] and that α-synuclein-containing Lewy body-like inclusions are found in PD patients with dementia [49]. Cerebral spinal fluid evaluation of PD patients with dementia reveals an underlying AD pathology in PD patients with dementia – high TAU, and phospho-Tau and a conditionally elevated β-amyloid protein [21].

    • These findings do not necessarily provide conclusive support for the central hypothesis describing the BACE1/β-amyloid protein as the countermeasure to metal toxicity but it does provide insight on how metal toxicity such as copper may be linked in the PD and AD models. In a theoretical case of the proposed new AD paradigm the BACE1/β-amyloid protein countermeasure may have saved the cell from copper-induced α-synuclein cross-linking thus thwarting the pathology from taking the path to α-synuclein aberration and phenotypic manifestation as PD. However, during the course of executing the successful BACE1/β-amyloid protein countermeasure, extraneuronal amyloid plaque accumulation occurs; with the signatures of α-synuclein-containing Lewy body structures as found by Suh and Checler.

    • In due time, after a long preclinical phase that could last as long as two decades, additional exogenous or other endogenous factors could contribute compounding oxidative strain or sporadic mutations in trafficking or degradation processes might reach critical states and interrupt cell trafficking. An additive oxidative force that is environmental or an age related decline of endogenous antioxidants may add to the cell’s oxidative load to induce IL-1 accumulation and TAU hyperphosphorylation. At this compounded point, ROS and other free radical species escalate to incrementally induce IL-1 [67] and eventually this advances hyperphosphorylation of Tau [92], resulting in Tau dissociation from the cytoskeletal microtubule system and microtubule derailment.

    • In this theoretical scenario the BACE1/β-amyloid protein countermeasure will ultimately fail due to trafficking impediment and AD may manifest at clinical levels. This AD patient would (theoretically and in accordance with the findings) exhibit Lewy body structures with α-synuclein inclusions but also copper-containing amyloid plaque formations that present signatures of α-synuclein. Both AD and PD are characterized by α-synuclein inclusions in senile (amyloid) plaques and Lewy body formations respectively [77].

Evidence demonstrates that APP and the β-amyloid peptide cleaved from APP through sequential enzymatic actions accumulate in the plasma membrane but also migrate to accumulate in the mitochondrial membrane [108]. The proposed role of this β-amyloid peptide in accordance with the hypothesis is to chelate free metal toxicity in the mitochondria. Research indicates that damage to the mitochondria by this β-amyloid-induced membrane breach eventually leads to severely impaired neuron metabolism which is thought to precede clinical diagnosis and significantly predate the onset of AD symptoms [82]. However, it is proposed as a component of this hypothesis that the mitochondrial membrane breach only occurs when the β-amyloid protein fails in its primary biological role as a chaperone to translocate from the mitochondria its sequestered toxic metal.

  • (3)

    Key positioning statement of the hypothesis: In some cases of familial AD, APP processing is dramatically increased beyond what is typical to produce early onset symptoms of disease [18]. Presenilin 1 mutations are a cause of autosomal dominant Alzheimer’s disease. Presenilin 1 is the catalytic subunit of the γ-secretase enzyme and mutation interferes with cleavage of amyloid precursor protein [106].

    • This leads to pro-oxidative accumulation of β-amyloid protein. The oxidative result as proposed in the new paradigm, is a pro-oxidative accumulation of the metallo-chelated β-amyloid protein. The metal such as copper is the ultimate pro-oxidant. It is also proposed that in this familial case of disease, however, the incremental β-amyloid protein begins to compete intracellularly with the endogenous antioxidants SOD, CAT and GSH for the essential cofactor metals Mn, Cu, Zn and Fe (and in the case of GSH, selenium). This creates a pro-oxidative environment that leaves a rate limiting availability of the metals for the endogenous antioxidants. This is a different starting point for the disease than the sporadic variation.

    • In sporadic AD, the accumulation of toxic metal can initiate an incremental BACE1 activity through NF-kappa-B activation – a function of a genetically built in compensatory system (depicted in Fig. 5) designed to perform in opposition to or as compensation for metal or other oxidative toxicity. The incremental BACE1 activity due to presenilin-1 mutation in familial AD exacerbates the oxidative load in the neuron earlier than it does in the ROS (and heavy metal ion) escalated model that underlies the sporadic case of AD (model shown at Fig. 5).

By highlighting the role of metal toxicity and oxidation; supporting the hypothesis that BACE1 is a protective enzyme and that β-amyloid protein is in fact a chelating and chaperone peptide the research focus and treatment goal for AD is changed from inhibition of this BACE1/β-amyloid protein countermeasure to researching methods that support and prevent its derailment; researching ways to preserve its role to sequester toxic metal ions and trap and traffic them extracellularly to form relatively benign plaques. The countermeasure support that can be deployed concurrently as a preventive and therapeutic approach may include endogenous antioxidant induction through Nrf2 transcription factor activity, metal chelation therapies, localized mitigation of NF-kappa-B and IL-1 inhibition for reasons further supported in pages to come. The preventive and treatment strategy is designed to prevent BACE1/β-amyloid protein countermeasure over-burdening and derailment of trafficking.

While this presents a unique mechanism for the development of sporadic and familial AD, 95% of the AD cases, and defines a new role for BACE1 and β-amyloid protein it also sheds light on the application of testable protocols that can prevent premature advancement of age-related physical and metabolic changes that lead to non-AD neurodegeneration and cognitive decline as well. This mechanism also provides insight on and rationale for why there are amyloid and NFT manifestations in cases of traumatic brain injury (TBI), PD, and other injurious events to neurons such as ischemic injury that can accumulate to produce clinical symptoms of AD and its hallmarks later in life [33], [86], [100]. Studies demonstrate an ameliorated recovery state from injury as a function of APP and processing of this precursor protein to yield β-amyloid protein [107] further supporting the hypothesis presented herein.

Section snippets

Mitochondrial starting point

ATP synthesis generates metabolic exhaust in the form of reactive oxygen species (ROS) and other free radicals which are typically reduced by the endogenous antioxidant system involving CAT, SOD, GSH and other important free radical reducing agents. Research indicates that APP exhibits antioxidant properties [38] and β-amyloid peptide exhibits potent metal chelating and therefore indirect antioxidant properties [57]. In particular, β-amyloid protein has a high affinity for copper, aluminum,

Closer look at APP and β-amyloid protein residue sequence

To lend more credence to the paradigm shift and support the proposal that APP, BACE1 and β-amyloid peptide are efficacious protective countermeasures, research also shows that BACE1 cleavage yields more than just the β-amyloid protein; it also yields secreted APP with direct antioxidant properties [38]. Upon inspection of the APP amino acid sequence it is evident that this is a cysteine rich peptide. The role of cysteine is likely disulfide bridge formation for maintenance of protein

Amyloid precursor protein processing

Song et al. show that NF-kappa-B signaling up-regulates BACE1 expression [14]. Other related research shows that NF-kappa-B modulates GSK3 β (glycogen synthase kinase) which in turn, regulates BACE1 expression [65]. NF-Kappa-B is also implicated in elevated oxidative stress and inflammation in the brain. These are factors that also contribute to neuron death or apoptosis [113]. These AD researchers have led the charge to discovery setting the stage for the currently proposed new paradigm.

Uncontrolled ROS sets in motion uncontrolled disease

ROS is known to be a central activator of inflammation through various means including NF-kappa-B release and translocation to the nucleus [32] from its cytosolic complex where it induces transcription and subsequent IL-1 induction [36]. It has been demonstrated that IL-1, in turn, can in fact induce the phosphorylation of Tau [92].

In the context of the hypothesized new paradigm, this Tau phosphorylation could be the starting point for the hyperphosphorylation and dissociation of Tau from the

The key endogenous antioxidant system: SOD, CAT, GSH

In studies with SOD knockout mice mitochondrial oxidative damage accumulates rapidly to inhibit respiration and culminate in apoptosis. Normal mice, on the other hand, exhibit similar outcomes as age-related events that occur in a comparable manner to the dynamic seen in AD but much later in life as an age-related decline [56]. Much like these oxidative and mitochondrial events occur as functions of aging, it is well established that amyloid plaque and especially neurofibrillary tangle

Summary

AD is a multigenic disease – a complex neuroinflammatory disease caused by a combined action by multiple genetic mutations, lifestyle factors and environmental elements including a proposed contribution by transition metals. This comprehensive dynamic makes disease encoding and treatment difficult. In the case of AD, the proposed model points to preventive measures that must be applied early in the preclinical phase to prevent neuron damage and apoptosis. In the context of our proposed new

Significance of the new paradigm

  • (1)

    Highlights the role of metal toxicity and oxidation; supporting the BACE1/β-amyloid protein system is a genetically programmed protective countermeasure that is designed to compound the antioxidant activity of other endogenous antioxidant systems such as those that induce and regulate CAT, SOD1 and GSH.

  • (2)

    Highlights the role of β-amyloid protein as a chelating and chaperone peptide designed to protect the neuron from transition metal toxicity that can exacerbate oxidative load via the Fenton

Conflict of interest

The author hypothesis is not inspired by third party influence; financial or other.

Acknowledgment

Special thank you to William Jia.

References (113)

  • H.E. de Vries

    Nrf2-induced antioxidant protection: a promising target to counteract ROS-mediated damage in neurodegenerative disease?

    Free Radic Biol Med

    (2008)
  • M. Dumont et al.

    Neuroprotective strategies involving ROS in Alzheimer disease

    Free Radic Biol Med

    (2011)
  • L. Flohé

    Redox regulation of NF-kappa B activation

    Free Radic Biol Med

    (1997)
  • S.M. Gentleman

    β-Amyloid precursor protein (βAPP) as a marker for axonal injury after head injury

    Neurosci Lett

    (1993)
  • L. Giliberto

    Mutant presenilin 1 increases the expression and activity of BACE1

    J Biol Chem

    (2009)
  • G. Gloire

    NF-κB activation by reactive oxygen species: fifteen years later

    Biochem Pharmacol

    (2006)
  • Y. Goodman et al.

    Secreted forms of β-amyloid precursor protein protect hippocampal neurons against amyloid β-peptide-induced oxidative injury

    Exp Neurol

    (1994)
  • L. Goth et al.

    Hereditary catalase deficiencies and increased risk of diabetes

    Lancet

    (2000)
  • Q. Guo

    Secreted β-amyloid precursor protein counteracts the proapoptotic action of mutant presenilin-1 by activation of NF-κB and stabilization of calcium homeostasis

    J Biol Chem

    (1998)
  • S.M. Harrison

    BACE1 (β-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes

    Mol Cell Neurosci

    (2003)
  • M. Hashimoto

    Human recombinant NACP/α-synuclein is aggregated and fibrillated in vitro: relevance for Lewy body disease

    Brain Res

    (1998)
  • H. Houlden

    A novel presenilin mutation (M233V) causing very early onset Alzheimer’s disease with Lewy bodies

    Neurosci Lett

    (2001)
  • J.H. Jhoo

    β-Amyloid (1–42)-induced learning and memory deficits in mice: involvement of oxidative burdens in the hippocampus and cerebral cortex

    Behav Brain Res

    (2004)
  • A. Kontush

    Amyloid-β: an antioxidant that becomes a pro-oxidant and critically contributes to Alzheimer’s disease

    Free Radic Biol Med

    (2001)
  • J.R. Korenberg

    The Alzheimer amyloid precursor protein maps to human chromosome 21 bands q21. 105–q21. 05

    Genomics

    (1989)
  • V.M. Lee

    More than just two peas in a pod: common amyloidogenic properties of tau and α-synuclein in neurodegenerative diseases

    Trends Neurosci

    (2004)
  • D. Liu

    Elevation of hydrogen peroxide after spinal cord injury detected by using the Fenton reaction

    Free Radic Biol Med

    (1999)
  • Y. Luo

    BACE1 (β-secretase) knockout mice do not acquire compensatory gene expression changes or develop neural lesions over time

    Neurobiol Dis

    (2003)
  • M.P. Mattson

    Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the β-amyloid precursor protein

    Neuron

    (1993)
  • S. Melov

    Modeling mitochondrial function in aging neurons

    Trends Neurosci

    (2004)
  • J. Mutter

    Amalgam studies: disregarding basic principles of mercury toxicity

    Int J Hyg Environ Health

    (2004)
  • T. Nguyen

    Transcriptional regulation of the antioxidant response element Activation by Nrf2 and repression by MafK

    J Biol Chem

    (2000)
  • M. Ohno

    BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice

    Neurobiol Dis

    (2007)
  • S.R. Paik

    Metal-catalyzed oxidation of α-synuclein in the presence of copper (II) and hydrogen peroxide

    Arch Biochem Biophys

    (2000)
  • D.M. Paresce

    Microglial cells internalize aggregates of the Alzheimer’s disease amyloid β-protein via a scavenger receptor

    Neuron

    (1996)
  • A. Paul

    Reduced mitochondrial SOD displays mortality characteristics reminiscent of natural aging

    Mech Ageing Dev

    (2007)
  • I. Piaceri

    Mitochondria and Alzheimer’s disease

    J Neurol Sci

    (2012)
  • J.L. Price

    The distribution of tangles, plaques and related immunohistochemical markers in healthy aging and Alzheimer’s disease

    Neurobiol Aging

    (1991)
  • D. Schubert et al.

    The role of iron in beta amyloid toxicity

    Biochem Biophys Res Commun

    (1995)
  • B.S. Shastry et al.

    Genes and susceptible loci of Alzheimer’s disease

    Brain Res Bull

    (1999)
  • A.Y. Shih

    Induction of the Nrf2-driven antioxidant response confers neuroprotection during mitochondrial stress in vivo

    J Biol Chem

    (2005)
  • K. Aoyama

    Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse

    Nat Neurosci

    (2006)
  • C.S. Atwood

    Copper mediates dityrosine cross-linking of Alzheimer’s amyloid-β

    Biochemistry

    (2004)
  • M.E. Bamberger

    A cell surface receptor complex for fibrillar β-amyloid mediates microglial activation

    J Neurosci

    (2003)
  • C. Behl

    Glucocorticoids enhance oxidative stress-induced cell death in hippocampal neurons in vitro

    Endocrinology

    (1997)
  • A. Binolfi

    Site-specific interactions of Cu (II) with α and β-synuclein: bridging the molecular gap between metal binding and aggregation

    J Am Chem Soc

    (2008)
  • P.H. Chan

    Role of oxidants in ischemic brain damage

    Stroke

    (1996)
  • C.-H. Chen

    Increased NF-κB signalling up-regulates BACE1 expression and its therapeutic potential in Alzheimer’s disease

    Int J Neuropsychopharmacol

    (2012)
  • L. Christiansen

    The catalase-262C/T promoter polymorphism and aging phenotypes

    J Gerontol A, Biol Sci Med Sci

    (2004)
  • M. Citron

    β-Secretase as a target for the treatment of Alzheimer’s disease

    J Neurosci Res

    (2002)
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