Neurodegenerative disorders affect millions of people worldwide, and this number is expected to increase substantially with rising life expectancy and population growth. Major efforts have been directed toward understanding the etiology of neurodegenerative conditions, but the challenge remains to elucidate molecular mechanisms underlying the onset and progression of neurodegeneration. Recent studies have identified multiple genetic mutations and risk factors associated with dementia and neurodegeneration, but additional causes are likely involved (Fu and Ip, 2023; Pihlstrøm et al., 2017; Bertram and Tanzi, 2005; Hardy and Orr, 2006). Aging is a major risk factor for many neurodegenerative disorders and plays a key role in disease emergence and progression (Azam et al., 2021; Saikumar and Bonini, 2021). Other significant risk factors include environmental insults that can evoke neuropathological processes, which may be latent at first but surface with aging to disrupt various aspects of brain structure and function, leading to neurodegenerative conditions (Brown et al., 2005; Gupta and Sen, 2016). Physical blows to the head are known to cause symptoms related to immediate brain injury, but even seemingly innocuous head impacts are strongly linked to brain dysfunction and degeneration later in life (Gupta and Sen, 2016; Brett et al., 2022; Ntikas et al., 2022). It is thus crucial to understand the aberrant processes triggered by these mild physical insults that may be initially ‘hidden’ but can give rise to later neurodegenerative conditions. Furthermore, sex differences have been documented in many degenerative diseases, including chronic brain degeneration following mild traumatic brain injury (Yue et al., 2019; Berz et al., 2013; Gupte et al., 2019). How sex and age contribute to an individual’s response to mild brain disturbances and modify the risk for neurodegeneration remains to be fully understood.

The fruit fly, Drosophila melanogaster, represents an excellent and tractable model organism for dissecting fundamental disease mechanisms, including neurodegeneration (Hirth, 2010; Lessing and Bonini, 2009; Petersen and Wassarman, 2012; McGurk et al., 2015). Importantly, the fruit fly’s relatively short lifespan enables longitudinal interrogation of disease progression from the initial trigger to the late-life emergence of neurodegenerative conditions such as Alzheimer’s disease, amyotrophic lateral sclerosis, and frontotemporal dementia (McGurk et al., 2015; Pandey and Nichols, 2011; Yuva-Aydemir et al., 2018; Bolus et al., 2020; Prüßing et al., 2013). Recently, several Drosophila head injury models have been developed that recapitulate key findings from traumatic brain injury (TBI) in humans and other preclinical models, revealing significant insights into the potential molecular and genetic underpinnings of injury responses (Barekat et al., 2016; Katzenberger et al., 2013; Sun and Chen, 2017; Saikumar et al., 2020; van Alphen et al., 2022; Ye et al., 2023; Behnke et al., 2021b). We recently developed a novel Drosophila model (HIFLI: Headfirst Impact FLy Injury) in which mild repetitive head-specific impacts can be delivered to multiple awake and unrestricted adult flies of both sexes (Behnke et al., 2021b). In this study, we utilized the HIFLI model to deliver a milder version of repetitive head trauma, which eliminates potentially confounding effects from injury-induced death and enables us to interrogate sex and age-at-injury contributions to the emergence of brain deficits throughout the entire lifespan. Our data show that exposure to this milder form of head trauma elicits minimal acute deficits but causes profound brain-associated behavioral deficits and brain degeneration that only emerge later in life. These late-life neurodegenerative conditions are further exacerbated by increasing age-at-injury and disproportionately elevated in mated females. We further identify that sex peptide signaling involved in female reproduction plays a key role in elevated female neurodegeneration after mild head trauma. Finally, RNA sequencing data suggest that the chronic suppression of innate immune defense networks in mated females may mediate the elevated vulnerability to neurodegeneration after mild head trauma. Together, our results further establish Drosophila as an excellent model system to investigate lifelong neurodegenerative conditions, highlight that sex and age significantly contribute to trauma recovery and outcome, and support the notion that physical insults to the head, even very mild ones, pose a major threat for brain health.

An emerging body of evidence suggests that early exposure to repetitive mild head trauma increases the risk of developing neurodegenerative conditions later in life. However, the underlying mechanisms remain unclear. In this study, we take advantage of the short lifespan and powerful genetic tools of D. melanogaster, in combination with our headfirst impact model (Behnke et al., 2021b), to investigate how early exposure to a very mild form of repetitive head trauma leads to late-life neurodegeneration. Previously, we showed that mild repetitive injuries can elicit degenerative phenotypes in both male and female flies, but female flies appear more vulnerable to the injuries (Behnke et al., 2021b). Our current study has further substantiated the previous findings by examining different age-at-injury cohorts and demonstrating their age-dependent and sexually dimorphic responses to a very mild form of repetitive head impacts. Furthermore, we discovered a strong link between SP signaling and injury-induced neurodegeneration in females. Compared to males, virgin females, and SP⁰-mated females, female flies mated to wildtype males were much more vulnerable to developing sensorimotor deficits and brain degeneration following injury exposure. This demonstrates, for the first time, the convergence and interaction of two supposedly separate pathways, namely the pathophysiological mechanisms elicited by mild head injury and the post-mating responses mediated by SP exposure. While activation of either one of these pathways was insufficient to generate neurodegenerative effects in females, their combination facilitated the emergence of quantifiable brain deficits. These findings provide an important foundation to further investigate the molecular and cellular mechanisms underlying sex differences in injury responses and neurodegeneration.

Sex-related differences have been documented in many medical conditions, including neurodegenerative disorders (Vegeto et al., 2020; Cerri et al., 2019; Nebel et al., 2018; Podcasy and Epperson, 2016) and neurotrauma of various severities (Yue et al., 2019; Gupte et al., 2019; Rauen et al., 2021). Sex differences include anatomical differences, sex gonadal hormones, and immunological responses, all of which presumably affect vulnerability to injury. In fact, there seems to be a growing consensus concerning sex-dependent effects in response to TBI, though clinical and preclinical findings are inconsistent. While female sex is more often associated with worse outcomes in human TBI studies, in preclinical TBI studies it is more frequently associated with better outcomes and neuroprotection after TBI (Gupte et al., 2019). Part of this disparity may be attributed to differences in injury severity and animal model, but the underlying drivers of sex differences in brain injury responses and neurodegenerative conditions remain to be fully elucidated. While sex differences in insects inherently differ from that in humans, there are some similarities associated with reproduction and hormone regulation. Therefore, it is likely that some of the fundamental mechanisms revealed in Drosophila may be conserved in humans.

Mating elicits two major types of changes in female flies; increase in egg-laying and reduction in receptivity to mating (Liu and Kubli, 2003; Chapman et al., 2003). Sperm alone can induce a short-term post-mating response, but a sustained response (>7 days) requires SP (Liu and Kubli, 2003). SP signaling via SPR activation is believed to switch the female to a state that maximizes reproduction (Yapici et al., 2008), which is considered evolutionarily beneficial. However, SP exposure can jeopardize female survival by decreasing daytime sleep (Isaac et al., 2010; Garbe et al., 2016), altering the immune system (Schwenke and Lazzaro, 2017; Short and Lazzaro, 2010; Short et al., 2012; Peng et al., 2005), and increasing female susceptibility to age-dependent tumors (Regan et al., 2016). To our knowledge, the current study is the first to directly show that SP-signaling can elevate vulnerability to injury-induced neurodegeneration in female flies. While mammals do not have SP, reproduction in females is known to dramatically alter metabolism, immune system, hormones, and neurobiology, all of which are vital for maintaining pregnancy. A connection between increased risk for neurodegeneration and hormonal changes associated with reproduction has been suggested in humans and other mammals (Xiong et al., 2022; Gilsanz et al., 2019; Jang et al., 2018). There are also contradictory findings, where female sex hormones are found to be neuroprotective (Ha et al., 2007; Song et al., 2020). These findings highlight the need for further animal studies with better controls of hormonal and reproductive cycles.

The current study also examines how aging affects response to mild head injury. In humans, age is one of the strongest outcome predictors for complications following head trauma, including mild trauma (Moretti et al., 2012; Jacobs et al., 2010; Bittencourt-Villalpando et al., 2021). Though the cause of injury may differ, older age is consistently associated with an increased incidence of head trauma, a slower overall recovery process, as well as greater morbidity and mortality following injury (Abdulle et al., 2018; Mosenthal et al., 2004). Consistent with these observations, we show that flies exposed to vmHT at older ages developed neurodegenerative deficits at a much faster rate than flies injured at younger ages. Our finding that aging accelerates injury-induced neurodegeneration is also supported by findings in humans and other animal models (Doust et al., 2021; Rowe et al., 2016; Ojo et al., 2013), suggesting conserved pathways underlying aging-induced vulnerability. Previous studies have suggested that mitochondrial function (Cui et al., 2012; Chistiakov et al., 2014) and immune function (Weyand and Goronzy, 2016; Haynes, 2020) decline with aging. Given that mitochondrial dysfunction (Cheng et al., 2012; Kim et al., 2017) and compromised immune responses Needham et al., 2019; Verboon et al., 2021 have also been implicated in TBI-induced brain dysfunction and degeneration, future work using our mild injury paradigm should investigate their contributions to aging-increased vulnerability and the development of neurodegeneration in response to head trauma.

Sex differences in aging are conserved across species. In line with this, we demonstrated sex differences in aging-associated vulnerability. While increasing age-at-injury in mated females is generally associated with more severe neurological deficits, females injured on D17 exhibit similar degrees of climbing deficits and vacuolation to those injured on D31, suggesting a possible plateau (Figure 3A). On the other hand, male flies are very resilient to vmHT at younger ages (D3 and D17), displaying little to no phenotypes even on D45 (Figure 3A). However, at the advanced age of 31 days post-eclosion, exposure to vmHT drastically accelerates neurodegeneration in the male brain, resulting in deficits similar to that of mated females of the same injury group (Figure 3B and E). As flies age, male flies seem to show a larger decline in resistance to injury-induced neurodegeneration than females. This finding is supported by work studying sex differences in immune senescence (Kubiak and Tinsley, 2017). In males, this is believed to occur principally due to age-related deterioration in barrier defenses, whereas in females this largely manifests in decreases in innate immunity. Older males may have a weaker exoskeletal defense system, making them more vulnerable to the effects of injury.

To gain some insights into the molecular mechanisms underlying the sexually dimorphic, late-life emergence of neurodegenerative conditions after early exposure to vmHT, we surveyed the transcriptomic landscapes of fly brains with and without vmHT exposure. We were specifically interested in identifying genes whose changes in expression might underlie the observed sex differences between male and mated females, as well as between females of varying reproductive status. Across all conditions and timepoints, we found that the injuries (regardless of age) elicited a very small number of differentially expressed genes that skewed toward decrease in expression. This was initially surprising, because previous Drosophila TBI work using the same RNA extraction protocol and sequencing company had reported large numbers of both immediate and lasting gene activation (Byrns et al., 2021). When we compared sham males and females at the acute timepoint, we found robust sex-specific gene expression (data not shown) and distinct clustering by sex in our PCA (Figure 6B). This confirmed the validity of our data and subsequent analyses and suggested that the small number of differentially expressed genes was likely due to the mild nature of our injury paradigm. Furthermore, it is possible that not all flies experienced increased neurodegeneration following the mild injuries, which could mask transcriptomic changes due to injury-induced neurodegeneration. Unlike other work utilizing a more severe injury paradigm (Byrns et al., 2021), we did not find any acute gene changes that persisted until the very chronic timepoint of 6 weeks following injury, suggesting that mild injury may induce dynamic transcriptomic changes throughout a fly’s lifespan. Additionally, cellular mechanisms that directly contribute to the development of neurodegenerative conditions may not be immediately active following injury; instead, they may be revealed by aging. To better understand the connections and interactions between acute and chronic changes in the transcriptome, future studies may further characterize these dynamic changes at multiple timepoints throughout the fly’s lifespan.

Previous work using a mild injury model has shown that AMP expression is elevated in the brain immediately following injury (in the first 12 hr), returned to baseline at 24 hr post-injury, and then elevated again 1 week post-injury (Barekat et al., 2016). This suggests that persistent elevation of AMP expression levels and the activation of the innate immune system at a chronic timepoint contributes to neurodegeneration. For both mated females and males, our results comparing injured and sham flies at the acute timepoint (1 dpi) do not show any elevation of AMP or AMP-like genes, which is congruent with previous data. A small percentage of immune-related gene changes were identified at this time, but these changes were all biased towards an injury-induced suppression. However, at 6 weeks post-injury, we find that the injury paradigm overwhelmingly depressed AMP and AMP-like gene expression in both male and mated female brains but not in virgin and SP-null mated female brains. Interestingly, injury-induced suppression of Metchnikowin and Diptericin and increased expression of PPO2 observed at the chronic timepoint is correlated with female-specific late-life behavioral deficits and brain pathology. This finding is supported by a recent report that mated female flies exhibited decreased markers of oxidative stress following trauma, which could be due to immune suppression following a TBI-induced immune challenge (Jones et al., 2024). Additionally, work comparing bacterial infection in virgin, SP⁰-mated, and wildtype-mated females suggests that mating and particularly egg-laying reduce the female’s overall ability to defend against bacterial infections, leading to decreased expression of AMP genes after infections (Short et al., 2012). This process is mediated by increases in Juvenile Hormone (Schwenke and Lazzaro, 2017), which is known to suppress innate immune processes (Flatt et al., 2008). SP exposure also acutely activates the Toll-like receptor and immune deficiency (Imd) pathways in females, altering levels of Metchnikowin and Diptericin (Peng et al., 2005). Furthermore, even one instance of mating is sufficient to induce chronic immunosuppression (Gordon et al., 2022). These changes may compound injury-induced changes to disrupt immune homeostasis, leading to observed immunosuppression in mated females. At an advanced age, a decreased expression of AMPs suggests that the mated female fly’s innate defense may be worsened by injury, making them unable to mount a sufficient immune response to pathological insults and therefore more susceptible to infections and disease.

Our finding of the decreased expression of AMP genes at this very chronic timepoint of 6 weeks post-injury, in combination with other groups’ findings of short-term elevation of AMP genes, also suggests a temporally dynamic gene expression pattern in response to head injury. Though immune suppression in mated females seems to contribute to neurodegenerative phenotypes, it is not immediately clear why suppression of a different set of AMP genes was not sufficient for neurodegenerative phenotypes in males. Future work can utilize males injured at older ages or with a more severe paradigm to understand male-specific transcriptome changes that contribute to injury-induced neurodegenerative conditions. Finally, though our RNA-seq data is informative, we acknowledge that there is limited correlation between mRNA and protein levels. Clearly, future studies are needed to dissect the genetic components and molecular players involved in the sex-different development of neurodegenerative conditions after mild head trauma.

RNA sequencing data have been deposited in GEO under the access code GSE274136.

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Author details

1. Changtian Ye

   Department of Cell Biology, Emory University School of Medicine, Atlanta, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft, Project administration, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-5381-410X

2. Ryan Ho

   College of Art and Science, Emory University, Atlanta, United States

   Contribution

   Formal analysis

   Competing interests

   No competing interests declared

3. Kenneth H Moberg

   Department of Cell Biology, Emory University School of Medicine, Atlanta, United States

   Contribution

   Supervision, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-9820-5543

4. James Q Zheng

   1. Department of Cell Biology, Emory University School of Medicine, Atlanta, United States
   2. Department of Neurology, Emory University School of Medicine, Atlanta, United States
   3. Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, United States

   Contribution

   Conceptualization, Data curation, Software, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Project administration, Writing – review and editing

   For correspondence

   james.zheng@emory.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-8093-422X

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