Introduction
Alzheimer's disease (AD), a neurodegenerative condition, is characterized by deficient
synaptic plasticity, dramatic neuronal dysfunction, and massive neuronal loss. Apart
from familial or early-onset AD (5–10%), most AD cases are non-familial or late-onset/sporadic
(90–95%; Ballard et al., 2011) with a complicated etiology. Some competing theories
have been suggested regarding the cause of AD, such as the amyloid hypothesis (Hardy
and Allsop, 1991) and tau hypothesis (Mudher and Lovestone, 2002), but minimal data
on initial triggers are available despite intensive explorations over recent decades.
We summarized the published evidence into an opinion that deciphers how the multifaceted
adverse environmental factors drive the onset and development of AD. Etiological drivers
can be categorized as biotic stressors and abiotic stressors, with the latter category
divided into physical stressors and chemical stressors. Ultimately, biotic/abiotic
stressors can be integrated into reactive oxygen species (ROS)/oxidative stressors
and reactive nitrogen species (RNS)/nitrosative stressors that impact the transition
of neurons from dysfunction to death (Barone et al., 2011a,b; Butterfield et al.,
2014).
Our opinion on biotic/abiotic stress-triggered AD links the various stressors to the
genesis and progression of AD through a neuroinflammatory signaling cascade, which
initiates nuclear factor κB (NF-κB) and induces pro-inflammatory cytokines that evoke
potent ROS/RNS burst for neuronal/glial killing. To trigger AD, biotic stressors convey
the external biological signals via lipopolysaccharide (LPS)-toll-like receptor 4
(TLR4), LPS-receptor of advanced glycation end products (RAGE), and amyloid β peptide
(Aβ)/senile plaques (SP)-RAGE interactions (Yan et al., 1996; Yamamoto et al., 2011).
Alternatively, abiotic stressors transduce the external non-biological signals via
AGEs-RAGE, high-mobility group protein B1 (HMGB1)-RAGE, and Aβ/SP-RAGE interactions
(Mazarati et al., 2011; Horst et al., 2016). Specifically, hypothermia, as well as
anesthesia and aging that induce hypothermia, can execute a neurotoxic role to kill
neurons and glia via neurofibrillary tangles (NFTs) derived from hyperphosphorylated
Tau (p-Tau) (Carrettiero et al., 2015; Figure 1).
Figure 1
A hypothetical schematic of biotic/abiotic stress-triggered AD. Biotic stress from
brain, oral, or gut infection can activate NF-κB-primed neuroinflammatory cascades,
elicit ROS/RNS burst, and kill neurons and glia via LPS-TLR4/RAGE and Aβ/SP-RAGE interactions
and subsequent signaling. Abiotic stress encompassing physical stress (e.g., head
trauma, stroke, or irradiation) and chemical stress (e.g., metals, pesticides, solvents,
or neurotoxins) can also activate NF-κB-primed neuroinflammatory cascades, elicit
ROS/RNS burst, and kill neurons and glia via AGEs-RAGE, HMGB1-RAGE/TLR4, and Aβ/SP-RAGE
interactions and downstream signaling. Hypothermia, anesthetics, and aging, can exert
a neurotoxic effect upon exposure of neurons and glia to NFTs (the background figure
was adopted from the website https://zhidao.baidu.com/daily/view?id=5979).
Mounting evidence supports that LPS and interferon γ (IFN-γ) activate microglia to
induce a pro-inflammatory neurotoxic M1 phenotype, whereas interleukin 4 (IL-4), IL-10,
IL-13, and transforming growth factor β (TGF-β) activate microglia to give rise to
an anti-inflammatory neuroprotective M2 phenotype (Tang and Le, 2016). Interestingly,
we found that electric acupuncture can mimic mechanical wounding to firstly deteriorate
LPS-induced AD-like brain pathogenesis, but secondly ameliorate the progressive neurodegeneration
in a wounding-healing manner, suggesting a putative conversion from M1 microglia to
M2 microglia (He, 2016).
Biotic stress and AD
Biotic stressors refer to any potential infectious pathogens or opportunistic infectious
microbes, including Chlamydophila pneumoniae (Balin et al., 1998), Helicobacter pylori
(Kountouras et al., 2012), Toxoplasma gondii (Prandota, 2014), human immunodeficiency
virus (HIV; Borjabad and Volsky, 2012), and human cytomegalovirus (HCMV; Lurain et
al., 2013). An international team recently urged that cerebral pathogenic infections
by herpes simplex virus type 1 (HSV-1), C. pneumoniae, spirochetes, and fungi be considered
as candidate AD initiators (Itzhaki et al., 2016). Similarly, extracerebral infectious
pathogens were also considered as AD triggers; for example, oral pathogenic infections
by the periodontal bacteria Porphyromonas gingivalis and Actinomyces naeslundii were
identified as high-risk factors driving development toward AD (Noble et al., 2014;
Singhrao et al., 2015). A recent study on gut microbiota dysbiosis indicated that
intestinal microbiome alterations are related to the malfunctional motor phenotypes,
suggesting the overgrowth of intestinal commensal microbes (i.e., opportunistic infection)
acting as a neurodegenerative driver (Scheperjans et al., 2015).
Sulfate-reducing bacteria (SRB), such as the Gram-positive Firmicutes and Gram-negative
Proteobacteria, colonize 50% of human guts (Stewart et al., 2006). Among which Desulfovibrio
piger was shown as the most common SRB in a surveyed cohort of healthy US adults (Scanlan
et al., 2009). Chondroitin sulfate, a daily dietary nutrient available from livestock
and poultry products, can increase the abundance of sulfatase-free D. piger upon reducing
sulfate released from sulfatase-secreting Bacteroides thetaiotaomicron (Rey et al.,
2013), thereby raising the possibility of B. thetaiotaomicron degrading mucin in the
gut. Red meat containing heme can also nourish the mucin-degrading bacteria (e.g.,
Akkermansia muciniphila; Ijssennagger et al., 2015). These observations predisposed
that gut dysbiosis may lead to the thinned mucosal layers and permeable colon linings,
which boost LPS leakage from the gut and entry into the blood stream (Qin et al.,
2012).
Factors that link the leaky gut and serum LPS to neurodegenerative diseases include:
the plasma level of LPS in patients with neurodegenerative disease is three times
higher than in healthy persons (Zhang et al., 2009); and intraperitoneal injections
of LPS into mice cause a prolonged elevation hippocampal Aβ levels and lead to cognitive
deficits (Kahn et al., 2012). To this end, intranasal LPS infusion was successfully
used to establish a neurodegenerative model in rodents (He et al., 2013). According
to a recent introduction by Scheperjans (2016) on the relevance of gut microbiota
to Aβ deposition, germ-free APPSWE/PS1ΔE9 mice show mitigated amyloidosis in the brain
compared with conventional APPSWE/PS1ΔE9 mice. While colonization of germ-free APPSWE/PS1ΔE9
mice with harvested gut microbiota from conventional APPSWE/PS1ΔE9 mice aggravates
cerebral amyloidosis, colonization with gut microbiota from wild-type mice fails to
increase cerebral Aβ levels.
Evidence supporting a possible infectious origin of AD is also derived from the sequencing-classified
single nucleotide polymorphism (SNP) in apolipoprotein E gene (APOE), which is involved
in modulating the immune response and infectious susceptibility (Verghese et al.,
2011). Genome-wide association studies have revealed that several immune system components
including virus receptor genes serve as risk factors for AD (Licastro et al., 2011).
For example, cholesterol 25-hydroxylase (CH25H), catalyzing the generation of 25-hydroxycholesterol
(25OHC) and inducing the enhancement of innate antiviral immunity, is selectively
upregulated by virus infection (Blanc et al., 2013; Liu et al., 2013).
Abiotic stress and AD
An epidemiological study has associated an increased risk of AD with a medical history
of traumatic head injury (Webster et al., 2015). Moreover, brain inflammation seems
a common consequence of mechanical insults such as trauma and stroke (Fiebich et al.,
2014). Trauma can significantly increase expression of the alarmin HMBG1 (Horst et
al., 2016), which in turn activates an inflammatory cascade by stimulating multiple
receptors including RAGE and TLR4 (Mazarati et al., 2011). A recent study showed that
AD-like model mice, on a diet enriched in AGEs due to irradiation, exhibit significant
memory dysfunction, accompanied with the hippocampal deposition of insoluble Aβ42
fragment and AGEs (Lubitz et al., 2016). This latter finding was consistent with the
notion that Aβ can activate microglia and induce neurotoxicity by RAGE binding (Yan
et al., 1996).
Many naturally occurring and synthesized chemicals such as heavy metals, pesticides,
bactericides, and solvents are ROS generators, and therefore are potential initiators
of AD (Chin-Chan et al., 2015). A recent study showed that magnetite from air pollution
might be an important risk factor for AD; particularly, those magnetite pollutant
particles that are <200 nm in diameter can enter the brain directly via the olfactory
bulb (Maher et al., 2016). Cyanobacteria or blue-green algae residing in the gut may
produce the neurotoxin β-N-methylamino-L-alanine (BMAA), which was implicated in the
development of AD (Banack et al., 2010; Brenner, 2013). Chronic dietary exposure to
BMAA was identified as a causal factor of neurodegeneration in the Chamorros villagers
on the Pacific island of Guam, and vervets (Chlorocebus sabaeus) fed with BMAA-dosed
fruit were observed to develop neurodegenerative diseases exhibiting Aβ and NFTs (Cox
et al., 2016).
It was highlighted that aggregation of p-Tau into NFTs or even development of tauopathies
seems an essential consequence of hypothermia as well as anesthetic-induced hypothermia
(Planel et al., 2007; Carrettiero et al., 2015). Due to reduced peripheral vasoconstriction,
mitigated heat production, and other reasons, the core body temperature of healthy
individuals over 60 years of age is 0.4°C lower than adults aged 20–60 years, suggesting
that aging should facilitate p-Tau formation by inducing cerebral hypothermia. It
was suggested that tau phosphorylation at later stages is mostly a consequence of
hypothermia although hyperphosphorylation at early stages may be due to the deregulation
of JNK and PP2A (El-Khoury et al., 2016).
Emerging evidence of Aβ as a responder to infection
In contrast to the conventional assertion of a causative role of Aβ in AD pathogenesis,
the peptide was surprisingly recognized as an antimicrobial peptide (AMP) with potent
activity against pathogenic infections (Soscia et al., 2010). Aβ has been confirmed
to protect mouse, nematode, and cell culture models of AD from fungal and bacterial
infections because propagating fibrils mediate the agglutination and eventual entrapment
of pathogens. Indeed, bacterial infection by Salmonella typhimurium in the brains
of transgenic AD mice results in accelerated Aβ deposition, which can co-localize
with invading bacteria (Kumar et al., 2016). It was recently reported that a long-term
antibiotic treatment regime inducing a prolonged change of gut microbiota decreases
Aβ deposition in the APPSWE/PS1ΔE9 mouse AD model. In the observation, soluble Aβ
levels were elevated, plaque-localized glial reactivity attenuated, and microglial
morphology altered, suggesting a diversity of gut microbiota regulating host innate
immunity, and impacting amyloidosis (Minter et al., 2016).
Aβ was also found to possess antiviral activity against HSV-1 and influenza A (White
et al., 2014; Bourgade et al., 2015, 2016). Interestingly, another AMP, β-defensin
1, has similarly shown overproduction in AD patients (Williams et al., 2013). An SNP
in human CH25H governs both AD susceptibility and Aβ deposition, implying Aβ induction
may be a 25OHC target, and also providing a potential mechanistic link between pathogenic
infection and Aβ accumulation (Papassotiropoulos et al., 2005; Lathe et al., 2014).
Aβ as a target for a potential AD remedy
Why Aβ progressively deposits remains largely unknown, but S-nitrosylation of cysteine
residues in Aβ-degrading enzymes might be relevant, and nitric oxide (NO) involved.
The impact from NO-mediated nitrosative stress was found to prompt the S-nitrosylation
of insulin-degrading enzyme (IDE) and dynamin-related protein 1 (Drp1) responsible
for Aβ degradation, thus inhibiting Aβ catabolism and hyperactivating mitochondrial
fission machinery. The raised Aβ levels and compromised mitochondrial bioenergetics
were shown to result in dysfunctional synaptic plasticity and synapse loss in cortical
and hippocampal neurons (Akhtar et al., 2016).
Interventions against AD involving eradicating Aβ from brain tissues hold promise
in avoiding microglial activation, immune attack, and neuron killing. It was shown
that aducanumab, a human monoclonal antibody that selectively targets the aggregated
Aβ, enters the brain, binds parenchymal Aβ, and reduces Aβ in a transgenic mouse AD
model, and that aducanumab even reduces brain Aβ in patients with prodromal AD after
1 year of monthly intravenous infusions (Sevigny et al., 2016).
Alternatively, prohibition of Aβ formation by impeding the cleavage of APP might also
prevent AD. An ongoing human trial is assessing the therapeutic value of the β-secretase
inhibitor solanezumab (Sheridan, 2015) although a clinical trial with the γ-secretase
inhibitor semagacestat failed just 1 year ago (De Strooper, 2014). The preliminary
data indicated that solanezumab can decrease cognitive decline in mild AD by about
30% in a clinical study recruiting 440 subjects (Reardon, 2015).
Prospectives
Considering Aβ as a pathogenic hallmark of AD, it is anticipated that treatments by
monoclonal antibodies to remove Aβ or block APP cleavage would justify optimism and
show progress in clinical trials. However, Aβ is unlikely an initiator, and more likely
a mediator of AD, so Aβ-targeted interventions should not be an eventual solution
to attenuating progressive aggravation toward AD. Once infectious agents have been
verified as the primordial etiological cues leading to AD, the more practical medications
treating AD should at least include, for example, anti-infection agents such as minocycline
(El-Shimy et al., 2015; Budni et al., 2016), anti-inflammation agents such as anhydroexfoliamycin
(Leirós et al., 2015) or rapamycin (Siman et al., 2015), and anti-oxidation agents
such as allicin (Zhu et al., 2015). With similar importance, modulation of gut microbiota
from dysbiosis to homeostasis for the early-phase prophylaxis of AD through personalized
diet and prebiotic/probiotic supplementation should also be addressed (Hu et al.,
2016).
Author contributions
QPZ wrote the manuscript. CQL, QZ, and QW critically reviewed the manuscript. All
authors read and approved the final version of the manuscript.
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.