Estrogen Enhances Dendrite Spine Function and Recovers Deficits in Neuroplasticity in the prpTDP-43A315T Mouse Model of Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) attacks the corticomotor system, with motor cortex function affected early in disease. Younger females have a lower relative risk of succumbing to ALS than males and older females, implicating a role for female sex hormones in disease progression. However, the mechanisms driving this dimorphic incidence are still largely unknown. We endeavoured to determine if estrogen mitigates disease progression and pathogenesis, focussing upon the dendritic spine as a site of action. Using two-photon live imaging we identify, in the prpTDP-43A315T mouse model of ALS, that dendritic spines in the male motor cortex have a reduced capacity for remodelling than their wild-type controls. In contrast, females show higher capacity for remodelling, with peak plasticity corresponding to highest estrogen levels during the estrous cycle. Estrogen manipulation through ovariectomies and estrogen replacement with 17β estradiol in vivo was found to significantly alter spine density and mitigate disease severity. Collectively, these findings reveal that synpatic plasticity is reduced in ALS, which can be amelioriated with estrogen, in conjuction with improved disease outcomes.

LATE and potential estrogen-related risk factors collected 30 years earlier: The 90+ Study

“…TDP-43 is also the proteinopathy signature of ALS (19). Studies using ALS mouse models have shown that estrogen might protect neurons against TDP-43 pathology (20) and improve neuronal plasticity (21). Moreover, a study on TDP-25 cell lines demonstrated the effect of the selective estrogen receptor modulator raloxifene on enhancing the viability of 25-kDa C-terminal fragment of TDP-43 by enhancing autophagy and suppressing apoptosis (22).…”

Brain volumetric changes in menopausal women and its association with cognitive function: a structured review

“…Estrogen and progesterone have been regarded as neuroprotective hormones. Estrogen mediates morphological and neurochemical changes of the neural processes by stimulating brain-derived neurotrophic factor (BDNF; Luine and Frankfurt, 2013 ) and by transcription factors ( Arevalo et al, 2015 ), cell signaling ( Yang et al, 2020 ), neuronal growth ( Scharfman and MacLusky, 2006 ; Bustamante-Barrientos et al, 2021 ), dendritic spine densities ( Handley et al, 2022 ), synaptic organization ( Wang et al, 2018 ), and regulation of cholinergic systems ( Kwakowsky et al, 2016 ). Similarly, progesterone induce neuroprotection by activating the mitogen-activated protein kinase (MAPK) and protein kinase B (Akt) signaling pathways ( Singh and Su, 2013 ; Liu et al, 2022 ), inhibiting excitotoxicity ( Luoma et al, 2011 ), promoting myelin repair ( Engman et al, 2018 ), and exerting anti-inflammatory effects ( Aryanpour et al, 2017 ; De Nicola et al, 2018 ).…”