Ovarian Cycle Stages Modulate Alzheimer-Related Cognitive and Brain Network Alterations in Female Mice

Broestl, Lauren; Worden, Kurtresha; Moreno, Arturo J.; Davis, Emily Jane; Wang, Dan; Garay, Bayardo I.; Singh, Tanya; Verret, Laure; Palop, Jorge J.; Dubal, Dena B.

doi:10.1523/eneuro.0132-17.2018

Cited by 27 publications

(25 citation statements)

References 93 publications

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“…Although female rodents do not undergo menopause, they do experience a period of altered estrous cycling (Guimarães et al, 2015) followed by persistently low estrogen levels at old ages (Felicio et al, 1984), similar to peri-and post-menopause in women. Findings from these models are in agreement with two possibilities in humans: (1) reduced estrogen exposure in adult females exacerbates disease progression, as in J20 mice (Box 1) (Broestl et al, 2018); and/or (2) the organizational effects of sex hormones during neurodevelopment have lasting effects that increase susceptibility to neurodegenerative disease later in life, as in 3xTgAD mice (Box 1) (Carroll et al, 2010). For more information, we direct the reader to a review summarizing findings from LOAD animal models consistent and inconsistent with the sex differences observed in humans (Fisher et al, 2018).…”

Section: Findings From Animal Modelssupporting

confidence: 78%

Sex-dependent effect of APOE on Alzheimer's disease and other age-related neurodegenerative disorders

Gamache

Yun

Chiba‐Falek

2020

Disease Models &Amp; Mechanisms

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The importance of apolipoprotein E (APOE) in late-onset Alzheimer's disease (LOAD) has been firmly established, but the mechanisms through which it exerts its pathogenic effects remain elusive. In addition, the sex-dependent effects of APOE on LOAD risk and endophenotypes have yet to be explained. In this Review, we revisit the different aspects of APOE involvement in neurodegeneration and neurological diseases, with particular attention to sex differences in the contribution of APOE to LOAD susceptibility. We discuss the role of APOE in a broader range of age-related neurodegenerative diseases, and summarize the biological factors linking APOE to sex hormones, drawing on supportive findings from rodent models to identify major mechanistic themes underlying the exacerbation of LOAD-associated neurodegeneration and pathology in the female brain. Additionally, we list sex-by-genotype interactions identified across neurodegenerative diseases, proposing APOE variants as a shared etiology for sex differences in the manifestation of these diseases. Finally, we present recent advancements in ‘omics’ technologies, which provide a new platform for more in-depth investigations of how dysregulation of this gene affects the development and progression of neurodegenerative diseases. Collectively, the evidence summarized in this Review highlights the interplay between APOE and sex as a key factor in the etiology of LOAD and other age-related neurodegenerative diseases. We emphasize the importance of careful examination of sex as a contributing factor in studying the underpinning genetics of neurodegenerative diseases in general, but particularly for LOAD.

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Section: Findings From Animal Modelssupporting

confidence: 78%

Sex-dependent effect of APOE on Alzheimer's disease and other age-related neurodegenerative disorders

Gamache

Yun

Chiba‐Falek

2020

Disease Models &Amp; Mechanisms

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“…This phenotypic difference between male and female 5xFAD mice is also consistent with the higher incidence of AD in female compared to male human subjects. Interestingly, TLQP-21 is also known to be involved in the regulation of the reproductive cycle in female rodents [18,21], and Broestl and colleagues have observed that female hAPP mice in estrogendominant cycle stages have worsened AD-related network dysfunction and cognitive impairments, while in contrast, those in progesterone-dominant stages and after gonadectomy have attenuated AD-related deficits [104]. Failure to detect equivalent effects of TLQP-21 treatment in male and female 5xFAD could also reflect sex-related differences in microglial function, which could be associated with transcriptional and translational differences between male and female microglia, including in C3aR1 expression levels which are higher in males [105,106].…”

Section: Discussionmentioning

confidence: 99%

VGF-derived peptide TLQP-21 modulates microglial function through C3aR1 signaling pathways and reduces neuropathology in 5xFAD mice

Gaamouch

Audrain

Lin

et al. 2020

Mol Neurodegeneration

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Background: Multiomic studies by several groups in the NIH Accelerating Medicines Partnership for Alzheimer's Disease (AMP-AD) identified VGF as a major driver of Alzheimer's disease (AD), also finding that reduced VGF levels correlate with mean amyloid plaque density, Clinical Dementia Rating (CDR) and Braak scores. VGF-derived peptide TLQP-21 activates the complement C3a receptor-1 (C3aR1), predominantly expressed in the brain on microglia. However, it is unclear how mouse or human TLQP-21, which are not identical, modulate microglial function and/or AD progression. Methods: We performed phagocytic/migration assays and RNA sequencing on BV2 microglial cells and primary microglia isolated from wild-type or C3aR1-null mice following treatment with TLQP-21 or C3a super agonist (C3aSA). Effects of intracerebroventricular TLQP-21 delivery were evaluated in 5xFAD mice, a mouse amyloidosis model of AD. Finally, the human HMC3 microglial cell line was treated with human TLQP-21 to determine whether specific peptide functions are conserved from mouse to human. Results: We demonstrate that TLQP-21 increases motility and phagocytic capacity in murine BV2 microglial cells, and in primary wild-type but not in C3aR1-null murine microglia, which under basal conditions have impaired phagocytic function compared to wild-type. RNA sequencing of primary microglia revealed overlapping transcriptomic changes induced by treatment with TLQP-21 or C3a super agonist (C3aSA). There were no transcriptomic changes in C3aR1-null or wild-type microglia exposed to the mutant peptide TLQP-R21A, which does not activate C3aR1. Most of the C3aSA-and TLQP-21-induced differentially expressed genes were linked to cell migration and proliferation. Intracerebroventricular TLQP-21 administration for 28 days via implanted osmotic pump resulted in a reduction of amyloid plaques and associated dystrophic neurites and restored expression of subsets of Alzheimer-associated microglial genes. Finally, we found that human TLQP-21 activates human microglia in a fashion similar to activation of murine microglia by mouse TLQP-21. Conclusions: These data provide molecular and functional evidence suggesting that mouse and human TLQP-21 modulate microglial function, with potential implications for the progression of AD-related neuropathology.

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“…Several possible explanations may account for the combined effects of sex and APOE [27][28][29][30]. A potential mechanism could be that oestradiol promotes synaptic sprouting in response to injury through an APOE-dependent mechanism [27].…”

Section: Discussionmentioning

confidence: 99%

“…A potential mechanism could be that oestradiol promotes synaptic sprouting in response to injury through an APOE-dependent mechanism [27]. Additionally, oestrogen might promote neural function under normal conditions, but exacerbate dysfunction when network activity is disrupted [28].…”

Section: Discussionmentioning

confidence: 99%

Disease progression modelling from preclinical Alzheimer’s disease (AD) to AD dementia

Cho

Woo

Kim

et al. 2019

Preprint

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Background: To characterize the course of Alzheimer's disease (AD) over a longer time interval, we aimed to construct a disease course model for the entire span of the disease using two separate cohorts ranging from preclinical AD to AD dementia.Methods: We used longitudinal data from 127 participants with preclinical AD and 309 participants with mild cognitive impairments (MCI) due to AD from the Alzheimer's Disease Neuroimaging Initiative. In order to develop a model of progression from preclinical AD to AD dementia, we estimated Alzheimer's Disease Assessment Scale-Cognitive Subscale 13 (ADAS-cog 13) scores according to the follow-up time for each cohort, determined the time point at which the estimated scores of ADAS-cog 13 for the two cohorts first overlapped, and shifted the ADAS-cog 13 scores for the latter cohort at this time point to connect the two cohorts and to combine the data into a single unified progression course.Results: The estimated years for progression from the median ADAS-cog 13 score in the preclinical AD cohort (9.3 points) to the median ADAS-cog 13 score at the time of progression in the participants who progressed from preclinical AD to MCI due to AD (16.0 points) was 7.8 years. The estimated years for progression from preclinical AD to the median ADAS-cog 13 score at the time of progression in those who progressed from MCI to due AD to AD dementia (26.8 points) was 15.2 years. ADAS-cog 13 scores deteriorated most rapidly in female APOE ε4 carriers and most slowly in male APOE ε4 noncarriers ( p < 0.001).Conclusion: Our results suggest that disease progression modelling from preclinical AD to AD dementia may help clinicians to estimate where patients are in the disease course and provide information on variation in the disease course by sex and APOE ε4 status. Background Understanding the course of disease progression across the whole Alzheimer's disease (AD) continuum including preclinical AD, mild cognitive impairment (MCI) due to AD, and AD dementia will help in designing clinical trials to test preventative interventions. Some studies have investigated the progression in preclinical AD [1], MCI due to AD [2] and AD dementia [3] separately. However, their Follow up month, median (IQR) 48 (24-72) 48 (36-60) ADAS-cog 13 median (IQR) 9.3 (6.7-12.0)* 17 (12.0-21.0)* Conversion to MCI due to AD, no (%) 37 (29.1) AD dementia, no (%) 13 (10.2) 134 (43.4) Age, education, ADAS-cog 13 and month of follow-up are expressed as median (IQR). Categorical variables are expressed as no (%). Statistical analyses are performed with Chi-squared tests for APOEε4 carriers and sex. Mann Whitney test for age, education and ADAS-cog 13. *p < 0.05 between preclinical AD vs. MCI due to AD Abbreviations: AD = Alzheimer's Disease; ADAS-cog = Alzheimer's Disease Assessment Scale-cognitive subscale; APOE = Apolipoprotein E; IQR = interquartile range; MCI = mild cognitive impairment Disease progression modelling from preclinical AD to AD dementiaThe median ADAS-cog 13 score was 16.0 points at the time of progressio...

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Ovarian Cycle Stages Modulate Alzheimer-Related Cognitive and Brain Network Alterations in Female Mice

Abstract: Visual Abstract

Cited by 27 publications

References 93 publications

Sex-dependent effect of APOE on Alzheimer's disease and other age-related neurodegenerative disorders

Sex-dependent effect of APOE on Alzheimer's disease and other age-related neurodegenerative disorders

VGF-derived peptide TLQP-21 modulates microglial function through C3aR1 signaling pathways and reduces neuropathology in 5xFAD mice

Disease progression modelling from preclinical Alzheimer’s disease (AD) to AD dementia

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