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.

Two-thirds of approximately 5 million Americans living with Alzheimer's disease (AD) are women, and a higher incidence of AD has been observed in postmenopausal women with lower serum 17β-estradiol (E2) levels. Additionally, patients with aromatase/estrogen inhibition often experience a greater amount of cognitive decline. Therefore, this proposal meets the critical needs as it will examine the underlying mechanisms and evaluate the therapeutic efficacy of non-invasive pulsed laser therapy for the treatment of cognitive deficits following the down-regulation and/or inhibition of brain aromatase.