Hyperbaric oxygen therapy as a new treatment approach for Alzheimer’s disease (AD):
Alongside the increase in life expectancy, the prevalence of age-related disorders,
such as neurodegenerative diseases, is on the rise. For example, AD, the most common
form of dementia in the elderly, accounts for 60–80% of all dementia cases. However,
there is presently no cure for this disease and no effective treatment that would
slow disease progression despite billions of dollars invested in drug development.
As AD is a complex disease, the development of effective and specific drugs is difficult.
Thus, examining alternative treatments that target several disease-related pathways
in parallel is of the utmost importance. Hyperbaric oxygen treatment (HBOT) is the
medical administration of 100% oxygen at environmental pressure greater than 1 atmosphere
absolute (ATA). HBOT has been shown to improve neurological functions and life quality
following neurological incidents such as stroke and traumatic brain injury, and to
improve performance of healthy subjects in multitasking. The current perspective describes
a recent study demonstrating that HBOT can ameliorate AD-related pathologies in an
AD mouse model, and provides unique insights into HBOT’s mechanisms of action. Old
triple-transgenic model (3xTg)-AD mice were exposed to 14 days of HBOT and showed
reduced hypoxia and neuroinflammation, reduction in beta-amyloid (Aβ) plaques and
phosphorylated tau, and improvement in behavioral tasks. This and additional studies
have shown that cerebral ischemia is a common denominator in many of the pathological
pathways and suggests that oxygen is an important tool in the arsenal for our fight
against AD. Given that HBOT is used in the clinic to treat various neurological conditions,
we suggest that this approach presents a new platform for the treatment of AD.
Dementia and AD: Dementia, a disorder characterized by chronic deterioration of cognitive
function, affects 47.5 million people worldwide. AD is the most common form of dementia
in the elderly, accounting for most of the cases. Although several drugs have been
approved for AD patients, they have limited effects on disease progression and fail
in the recovery of cognitive capacity once the disease has progressed. Therefore,
there is a real need for new and early interventions.
AD is characterized by extracellular senile plaques, formed by deposits of beta-amyloid
(Aβ) and intracellular neurofibrillary tangles formed by the accumulation of abnormally
phosphorylated tau protein, which ultimately lead to loss of synapses and degeneration
of neurons. Hypoxia-lack of oxygen in the tissue has a major role in AD pathogenesis.
The association between hypoxia and dementia emerged from epidemiological studies,
showing increased incidence of dementia in ischemic stroke patients. Recent evidence
suggests that AD patients present reduced cerebral perfusion, which can be detected
in early stages of the disease, and declines further with disease progression (Binnewijzend
et al., 2013). Furthermore, cerebral hypoperfusion can lead to hypoxia, which has
been shown to promote AD pathogenesis through acceleration of Aβ accumulation, increasing
the hyperphosphorylation of tau, activating microglia and astroglia, inducing proinflammatory
cytokine secretion, increasing the generation of reactive oxygen species (ROS) and
facilitating loss of neurons (Zhang and Le, 2010).
While reduced levels of oxygen lead to pathological complications, higher oxygen levels
can improve or boost brain function. Studies have shown that in elderly (Kim et al.,
2013) healthy subjects, oxygen supplementation improves the subjects’ performance
in cognitive tasks and changes the electroencephalographic (EEG) pattern of brain
activity, indicating that oxygen is a rate-limiting factor in normal and disease-associated
cognitive function.
HBOT: HBOT—the medical administration of 100% oxygen at environmental pressure greater
than 1 ATA—has been used in the clinic for a wide range of medical conditions. One
of HBOT’s main mechanisms of action is more effective elevation of the partial pressure
of oxygen in the blood and tissues as compared to simple oxygen supplementation (Calvert
et al., 2007). Indeed, HBOT improved the performance of healthy subjects in both motor
and cognitive single tasks or in multitasking (cognitive and motor) compared to subjects
under normobaric conditions (Vadas et al., 2017).
This raises many questions regarding the cellular and molecular, as well as system-level
effects of HBOT on brain performance, and whether it can be used to reverse or reduce
pathologies in neurological disorders. At the cellular level, HBOT can improve mitochondrial
redox, preserve mitochondrial integrity, hinder mitochondrion-associated apoptotic
pathways, alleviate oxidative stress and increase levels of neurotrophins and nitric
oxide through enhancement of mitochondrial function in both neurons and glial cells
(Huang and Obenaus, 2011). Similarly, many studies have demonstrated a neuroprotective
effect of HBOT in both experimental ischemic brain injury and experimental traumatic
brain injury. Moreover, HBOT has been shown to significantly improve neurological
functions and life quality in stroke patients, even at chronic late stages, after
the stroke has already occurred (Efrati et al., 2013).
To further understand the underlying molecular mechanisms and changes following HBOT
in the context of AD, we recently examined the effects of HBOT on AD pathologies in
the 3xTg-AD mouse model (Shapira et al., 2018). We exposed 17-month-old 3xTg mice
to HBOT (administration of 100% oxygen at 2 ATA; HBO group) or normobaric air (21%
oxygen at 1 ATA; control group) for 60 minutes daily for 14 consecutive days. Following
this treatment, mice were subjected to a battery of behavioral tasks (Y-maze, open-field
test and object recognition test). In all of the behavioral tests, 3xTg mice showed
impaired performance compared to non-transgenic controls, and HBOT significantly improved
or restored 3xTg-treated mouse behavior. The impaired performance of 3xTg mice in
behavioral tasks was accompanied by a strong presence of hypoxia in the hippocampal
formation, and this was significantly reduced by HBOT (
Figure 1
).
Figure 1
Hypoxia and hyperbaric oxygen therapy (HBOT) effect on neurons and microglia.
Hypoxia (red), the lack of oxygen in the tissue, contributes to the accumulation of
amyloid plaques, phosphorylation of tau and loss of synapses and neurons that ultimately
leads to cognitive decline. HBOT (green) reduces hypoxia (elevates the partial pressure
of oxygen (pO2)), amyloid burden and tau phosphorylation, decreases the total levels
of GSK3β, and improves cognitive performance. Furthermore, HBOT induces a morphological
change in microglia near plaques to a more ramified state, reduces the secretion of
proinflammatory cytokines (interleukin (IL)-1β, tumor necrosis factor alpha (TNF-α))
and increases the secretion of antiinflammatory cytokines (IL-4, IL-10). GSK3β: Glycogen
synthase kinase 3β.
The improved performance in behavioral tasks following HBOT was also associated with
marked changes in the pathological hallmarks of AD. HBOT reduced the amyloid burden
in 3xTg mice by decreasing the number and size of Aβ plaques. Furthermore, HBOT attenuated
abnormal amyloid precursor protein (APP) processing, which leads to the excessive
generation of Aβ42 and formation of Aβ plaques. Specifically, HBOT reduced the levels
of β-secretase 1 (BACE1) and presenilin 1 (a component of γ-secretase), which promote
the amyloidogenic APP processing. This observation is in accordance with evidence
of hypoxia inducing Aβ generation by facilitating β- and γ-secretase cleavage of APP
(Li et al., 2009).
Apart from amyloid plaques, we showed that HBOT reduces the phosphorylation of tau
without changing the total level of tau protein. The reduction in tau phosphorylation
was associated with an elevated ratio of phosphorylated glycogen synthase kinase 3β
(GSK3β) at site Ser9 to total GSK3β protein, mainly due to a decrease in the total
levels of GSK3β (
Figure 1
). Elevated GSK3β levels have been associated with increased tau phosphorylation due
to hypoxia (reviewed in Zhang and Le, 2010).
Hypoxia has been shown to activate microglia and astroglia and to induce proinflammatory
cytokine secretion. The 3xTg-AD mice show high levels of cytokines and neuroinflammation.
Interestingly, HBOT reduced microgliosis, astrogliosis, and the secretion of proinflammatory
cytokines, such as interleukin (IL)-1β and tumor necrosis factor alpha (TNFα), and
increased the production of anti-inflammatory cytokines, such as IL-4 and IL-10 in
3xTg mice (
Figure 1
). Moreover, HBOT induced a morphological change in microglia near plaques to a more
ramified state, and increased microglial expression of scavenger receptor A and arginase
1, which are known to mediate Aβ clearance (Frenkel et al., 2013). These results suggest
that HBOT attenuates neuroinflammation and represses inflammatory mediators (
Figure 1
). This modulation of the immune system by HBOT is consistent with previous studies
investigating this treatment’s effect on other neurological conditions, such as traumatic
brain injury, stroke and brain ischemia.
Hypoxia is a major cause for generation of ROS, peroxidation of cellular membrane
lipids, cleavage of DNA, protein oxidation, and mitochondrial dysfunction (reviewed
in Zhang and Le, 2010). It was previously shown that elevation of oxygen in the brain
of AD rat models by HBOT increased the activity of antioxidant enzymes and led to
the suppression of oxidative damage and decreased neuronal degeneration, thus contributing
to the protective effect of HBOT in AD (Tian et al., 2012; Zhao et al., 2017).
Taken together, our results suggest that in the context of AD, oxygen is a rate-limiting
factor for tissue recovery and cognitive function, similar to other neurological conditions.
Implications for treatment of AD patients: The growing understanding of the importance
of oxygen in brain functionality under normal and diseased conditions marks it as
a key player in AD treatment. As such, HBOT emerges as a well-tolerated, safe and
effective platform to enhance brain oxygenation. Due to its neuroprotective effects,
HBOT is used to treat various neurological conditions associated with hypoxia (such
as stroke, ischemia and traumatic brain injury). Our recent findings lay the first
stone for the use of HBOT in the treatment of AD as well. Unfortunately, when AD is
clinically diagnosed, the patients already have significant brain atrophy, which means
significant tissue loss that cannot be recovered. Moreover, AD patients present different
pathological patterns and severities, making them a heterogeneous population. Therefore,
one of the most important challenges in the application of HBOT to the clinical setting
is to identify the subpopulation of patients which will benefit the most from the
treatment. The classical candidate for HBOT would be a patient in the early stages
of AD, before it is fully developed. Hence, early biomarkers for AD should be sought
(blood, cerebral spinal fluid, imaging, and cognitive indications) and measured routinely.
When deterioration in these measures is detected before significant functional decline,
HBOT should be applied. Early diagnosis of AD will enable treatment when irreversible
damage is still minimal, thereby maximizing the effect of HBOT.
In summary, we discussed the effects of HBOT on the pathology of the 3xTg mouse model
of AD. Application of HBOT in the clinic calls for further optimization to achieve
similar effects in human patients. Specifically, the optimal or ideal treatment should
be determined with respect to oxygen pressure, time of treatment, and sustainability
of the treatment. We expect that similar to other neurological disorders, HBOT will
show promising results in the treatment of AD.
This work was supported in part by the Israeli Ministry of Science, Technology and
Space to UA (Grant number 3-12069).