Exercise and estrogen: common pathways in Alzheimer's disease pathology

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease that is characterized by progressive declines in cognitive function. Current epidemiological data indicates significant sex-linked disparities, where females have a higher risk of developing AD compared to male counterparts. This disparity necessitates further investigations to uncover the pathological and molecular factors influencing these sex differences. Although the underlying pathways behind this observed disparity remain elusive, recent research points to menopausal estrogen loss as a potential factor. Estrogen holds a significant role in APP processing as well as overall neuronal health through the regulation of brain derived neurotrophic factor (BDNF) - a factor that is also reduced in post-menopausal women. BDNF is a known contributor to neuronal health, and its reduced expression is typically linked to AD disorders. Exercise is known to increased BDNF and may provide an accessible activity for post-menopausal women to reduce their risk of AD. This review aims to discuss the relationship between estrogen, exercise, and BDNF in AD pathology.

Voluntary wheel running alters markers of amyloid-beta precursor protein processing in an ovarian hormone depleted model

“…Both the reduction in sABPPα fragments and the increase in BACE1 activity are commonly associated with increased levels of AB peptides and subsequent plaques in patients with AD ( 15 , 25 , 48 ). Although we were unable to directly measure AB peptide content in our study, BACE1 is the rate-limiting enzymatic step involved with the amyloidogenic cascade and studies have demonstrated increases in AB peptide content following higher activity levels of BACE1 ( 3 , 12 , 15 , 43 , 49 ). Work from our lab has previously shown that BACE1 activity is lowered with exercise in male mice potentially explaining these compensatory effects we saw in the OVX VWR group ( 15 ).…”

“…Initially, it was thought that this was due to the longer lifespan of females, however, even after accounting for age, the difference between males and females is present ( 8 ). It is possible that this discrepancy is caused by the estrogen depletion that females experience during menopause ( 8 – 12 ). Estrogen is the most abundant ovarian hormone and is a regulator of brain-derived neurotrophic factor (BDNF), a protein that maintains neuronal plasticity and health.…”

“…The activation of the transcription factor c-AMP response element-binding protein (CREB) is an important regulator of BDNF gene expression and is downstream of both estrogen ( 8 – 10 , 12 ) and BDNF signaling ( 3 , 5 , 8 , 9 , 14 ). In models of estrogen loss such as an ovariectomized (OVX) mouse model, BDNF levels tend to be reduced indicating that estrogen plays a role in the expression of BDNF ( 9 , 10 ).…”

The effect of long-term exposure to heated tobacco products on the central nervous system using novel in vivo experimental methods

“…Although Aβ-dependent pathways play a key role in AD pathogenesis, Aβ-independent pathways are also known to be important [12,13]. The association between the endocrine system and AD pathogenesis has recently garnered attention [38,39]. The ndings collectively suggest that the health risks of HTPs via Aβ-independent pathways, such as those in the endocrine system, in AD pathogenesis are worth noting.…”

Hormonal regulation of metabolism—recent lessons learned from insulin and estrogen

“…Inflammation and satellite cell function are also estrogen sensitive and can contribute to muscle strength preservation [ 134 , 135 ]. Estrogen plays a crucial role in the processing of amyloid precursor protein (APP) and general neuronal health, which is partially via the modulation of brain-derived neurotrophic factor (BDNF), a factor that is similarly decreased in postmenopausal women and negatively associated with AD progression [ 128 , 129 ].…”