ABSTRACT
Alzheimer’s disease (AD) is the most common form of dementia in the United States, affecting over 5 million
Americans. Unfortunately, there are currently no effective therapeutic strategies to slow, halt, or reverse the
advance of the disease. As a noninvasive procedure, Low-level Laser Therapy (LLLT) or
photobiomodulation is widely practiced to stimulate healing, relieve pain, and reduce inflammation. Our
previous studies on AD animal models and our preliminary data on a novel and clinically relevant transgenic
rat model have shown that LLLT can strongly protect against AD pathological hallmarks and cognitive
decline. This exciting observation has led to hope that further studies of LLLT neuroprotection against AD
could potentially lead to new therapies in humans. The overall goal of the current proposal is to test the
neuroprotective and cognitive improvement effects of LLLT on AD pathology, and to elucidate the underlying
mechanisms. We hypothesize that leakage of blood hemoglobin (blood-Hb) into brain tissue through the
compromised blood brain barrier (BBB) during AD progression aggregates Aß plague formation, enhances
oxidative stress and inflammation, and accelerates tauopathy. Alongside this, AD-induced mitochondrial
fragmentation and energy depletion, as well as decreases in neuronal hemoglobin (Neu-Hb), weakens
cellular resistance to Aß toxicity. Collectively, AD induces extracellular Aß deposits, aberrant intracellular
mitochondrial fission and dysfunction, neurofibrillary tangles, and oxidative and inflammatory damage that
ultimately culminate in neurodegeneration and cognitive decline. However, we hypothesize that LLLT can
confer neuroprotective and cognitive benefits in AD pathology. We posit that these benefits result from
LLLT’s ability to preserve healthy mitochondrial fission/fusion dynamics, thereby promoting mitochondrial
function as well as enhancing endogenous heme biosynthesis. In addition, we propose that LLLT induced
shifts in mitochondrial dynamics will potentiate nuclear translocation of HIF-1a to induce the target gene
expression. On the one hand, the induced factors are able to protect and repair BBB damage, thereby
reducing Aß aggregation exacerbated by exogenous blood-Hb. On the other hand, HIF-1a-induced globin
can be assembled with mitochondrial-produced heme to form Neu-Hb to exert beneficial effects. The
proposed studies would advance the field by determining the potential efficacy of LLLT for protection of the
AD brain. Specific Aim 1 would test the hypothesis that LLLT exerts neuroprotection and improves
functional outcome in transgenic AD rats. Specific Aim 2 would test the hypothesis that preservation of
mitochondrial dynamics and restoration of mitochondrial function underlies LLLT’s neuroprotective abilities.
Specific Aim 3 would test the hypothesis that LLLT reduces Aß aggregation and increases neuronal
resistance/homeostasis via the activation of Mitochondria-HIF-1a-Hb pathway in AD pathological conditions.