Abstract
Alzheimer's disease (AD) is a growing global health concern that disproportionately impacts women.
Additionally, patients with aromatase/estrogen receptor inhibitors often experience cognitive decline. However,
the underlying pathophysiology and sexual dimorphic mechanisms are still not completely understood, and no
proven treatment or prevention is currently available. Our preliminary studies suggest that brain
aromatase/17β-estradiol (E2) declines significantly preceding the symptoms of AD dementia in rodent AD
models, and systemically inhibiting aromatase or brain-specific knockdown of aromatase further aggravates AD
progression, especially in females. Conversely, the retention of brain aromatase/E2 using exogenous E2
administration or pulsed photobiomodulation (PBM)/laser treatment can mitigate AD development and alleviate
cognitive impairment. Therefore, this proposal aims to elucidate the role of brain aromatase in AD development
and identify whether aromatase is a new target for PBM therapy for preventing and managing AD. Our central
hypothesis is that a decline in brain aromatase plays a causal role in the pathogenesis of AD and that pulsed
PBM can target the heme-iron-containing aromatase enzyme to improve its activity and preserve local brain E2
level, thereby promoting synaptogenesis and ameliorating cognitive decline in AD. To test these hypotheses,
we will first examine whether downregulation or inhibition of aromatase is associated with aggravated cognitive
decline and if PBM or E2 treatment prevent aromatase decline and cognitive deficits in a novel AD rat model.
Secondly, we will test if brain aromatase mediates the beneficial effects of PBM therapy on local E2 production
and cognitive improvements using different AD models. Third, we will determine if PBM enhances
synaptogenesis and spine formation via an aromatase/E2-irisin-BDNF signaling mechanism in both in vivo and
in vitro AD models. To accomplish our objective, we will use transgenic TgF344-AD and 3xTg-AD rodent
models, forebrain neuron-specific aromatase KO (FBN-Aro-KO) mice, and cross-generated FBN-Aro-KO AD
mice. Rat primary neuronal cultures exposed to PBM will also be employed to validate our hypothesis. Our
proposed research is both mechanistically and technically innovative as it will elucidate the efficacy of pulsed
PBM therapy in retaining brain aromatase/E2 homeostasis in different AD models while also identifying novel
signaling mechanisms for pulsed PBM therapy. In addition, our proposed research could offer an important
adjuvant therapy for patients with aromatase/estrogen receptor inhibitors. Therefore, this proposal has valuable
clinical novelty for the prevention and management of AD dementia and to explain the sex differences in AD
development.
