Clinical studies indicate that Alzheimer's disease (AD) disproportionately affects women in both disease prevalence and rate of symptom progression, but the mechanisms underlying this sexual divergence are unknown. Although some have suggested this difference in risk is a reflection of the known differences in longevity between men and women, mounting clinical and preclinical evidence supports women also having intrinsic susceptibilities toward the disease. Although a number of potential risk factors have been hypothesized to mediate these differences, none have been definitively verified. In this review, we first summarize the epidemiologic studies of prevalence and incidence of AD among the sexes. Next, we discuss the most likely risk factors to date that interact with biological sex, including (1) genetic factors, (2) sex hormones (3) deviations in brain structure, (4) inflammation and microglia, and (5) and psychosocial stress responses. Overall, though differences in life span are likely to account for part of the divide between the sexes in AD prevalence, the abundance of preclinical and clinical evidence presented here suggests an increase in intrinsic AD risk for women. Therefore, future studies focusing on the underlying biological mechanisms for this phenomenon are needed to better understand AD pathogenesis in both sexes, with the eventual goal of sex-specific prevention and treatment strategies.

Chronic pain often occurs in the elderly, particularly in the patients with neurodegenerative disorders such as Alzheimer’s disease (AD). Although studies indicate that chronic pain correlates with cognitive decline, it is unclear whether chronic pain accelerates AD pathogenesis. In this review, we provide evidence that supports a link between chronic pain and AD and discuss potential mechanisms underlying this connection based on currently available literature from human and animal studies. Specifically, we describe two intertwined processes, locus coeruleus noradrenergic system dysfunction and neuroinflammation resulting from microglial pro-inflammatory activation in brain areas mediating the affective component of pain and cognition that have been found to influence both chronic pain and AD. These represent a pathological overlap that likely leads chronic pain to accelerate AD pathogenesis. Further, we discuss potential therapeutic interventions targeting noradrenergic dysfunction and microglial activation that may improve patient outcomes for those with chronic pain and AD.

Major Depressive Disorder is a prevalent psychiatric condition with limited therapeutic options beyond monoaminergic therapies. Although effective in some individuals, many patients fail to respond adequately to existing treatments and new pharmacologic targets are needed. HCN channels regulate excitability in neurons and blocking HCN channel function has been proposed as a novel antidepressant strategy. However, systemic blockade of HCN channels produces cardiac effects that limit this approach. Knockout (KO) of the brain-specific HCN channel auxiliary subunit TRIP8b also produces antidepressant-like behavioral effects and suggests that inhibiting TRIP8b function could produce antidepressant-like effects without affecting the heart. We examined the structural basis of TRIP8b-mediated HCN channel trafficking and its relationship to antidepressant-like behavior using a viral rescue approach in TRIP8b KO mice. We found that restoring TRIP8b to the hippocampus was sufficient to reverse the impaired HCN channel trafficking and antidepressant-like behavioral effects caused by TRIP8b KO. Moreover, we found that hippocampal expression of a mutated version of TRIP8b further impaired HCN channel trafficking and increased the antidepressant-like behavioral phenotype of TRIP8b KO mice. Thus, modulating the TRIP8b-HCN interaction bidirectionally influences channel trafficking and antidepressant-like behavior. Overall, our work suggests that small molecule inhibitors of the interaction between TRIP8b and HCN should produce antidepressant-like behaviors and could represent a new paradigm for the treatment of Major Depressive Disorder.

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Behavioral and psychological symptoms of dementia (BPSD) afflict the vast majority of patients with dementia, especially those with Alzheimer’s disease (AD). In clinical settings, patients with BPSD most often do not present with just one symptom. Rather, clusters of symptoms commonly co-occur and can, thus, be grouped into behavioral domains that may ultimately be the result of disruptions in overarching neural circuits. One major BPSD domain routinely identified across patients with AD is the hyperactivity–impulsivity–irritiability–disinhibition–aggression–agitation (HIDA) domain. The HIDA domain represents one of the most difficult sets of symptoms to manage in AD and accounts for much of the burden for caregivers and hospital staff. Although many studies recommend non-pharmacological treatments for HIDA domain symptoms as first-line, they demonstrate little consensus as to what these treatments should be and are often difficult to implement clinically. Certain symptoms within the HIDA domain also do not respond adequately to these treatments, putting patients at risk and necessitating adjunct pharmacological intervention. In this review, we summarize the current literature regarding non-pharmacological and pharmacological interventions for the HIDA domain and provide suggestions for improving treatment. As epigenetic changes due to both aging and AD cause dysfunction in drug-targeted receptors, we propose that HIDA domain treatments could be enhanced by adjunct strategies that modify these epigenetic alterations and, thus, increase efficacy and reduce side effects. To improve the implementation of non-pharmacological approaches in clinical settings, we suggest that issues regarding inadequate resources and guidance for implementation should be addressed. Finally, we propose that increased monitoring of symptom and treatment progression via novel sensor technology and the “DICE” (describe, investigate, create, and evaluate) approach may enhance both pharmacological and non-pharmacological interventions for the HIDA domain.

Clinical studies indicate that Alzheimer's disease (AD) disproportionately affects women in both disease prevalence and severity, but the mechanisms underlying this sex divergence are unknown. Though some have suggested this difference in risk is a reflection of known differences in longevity between men and women, mounting clinical and preclinical evidence supports women also having intrinsic susceptibilities towards the disease. While a number of potential risk factors have been hypothesized to affect these differences in risks, none have been definitively verified. In this review, we discuss a novel hypothesis whereby women's susceptibility to chronic stress also mediates increased risk for AD. As stress is a risk factor for AD, and women are twice as likely to develop mood disorders where stress is a major etiology, it is possible that sex dimorphisms in stress responses contribute to the increase in women with AD. In line with this, sex divergence in biochemical responses to stress have been noted along the hypothalamic-pituitary-adrenal (HPA) axis and among known molecular effectors of AD, with crosstalk between these processes also being likely. In addition, activation of the cortical corticotrophin-releasing factor receptor 1 (CRF1) signaling pathway leads to distinct female-biased increases in molecules associated with AD pathogenesis. Therefore, the different biochemical responses to stress between women and men may represent an intrinsic, sex-dependent risk factor for AD.

Background The role of microglia in Alzheimer’s disease (AD) pathogenesis is becoming increasingly important, as activation of these cell types likely contributes to both pathological and protective processes associated with all phases of the disease. During early AD pathogenesis, one of the first areas of degeneration is the locus coeruleus (LC), which provides broad innervation of the central nervous system and facilitates norepinephrine (NE) transmission. Though the LC-NE is likely to influence microglial dynamics, it is unclear how these systems change with AD compared to otherwise healthy aging. Methods In this study, we evaluated the dynamic changes of neuroinflammation and neurodegeneration in the LC-NE system in the brain and spinal cord of APP/PS1 mice and aged WT mice using immunofluorescence and ELISA. Results Our results demonstrated increased expression of inflammatory cytokines and microglial activation observed in the cortex, hippocampus, and spinal cord of APP/PS1 compared to WT mice. LC-NE neuron and fiber loss as well as reduced norepinephrine transporter (NET) expression was more evident in APP/PS1 mice, although NE levels were similar between 12-month-old APP/PS1 and WT mice. Notably, the degree of microglial activation, LC-NE nerve fiber loss, and NET reduction in the brain and spinal cord were more severe in 12-month-old APP/PS1 compared to 12- and 24-month-old WT mice. Conclusion These results suggest that elevated neuroinflammation and microglial activation in the brain and spinal cord of APP/PS1 mice correlate with significant degeneration of the LC-NE system.

Background Older patients can be especially susceptible to antipsychotic-induced side effects, and the pharmacodynamic mechanism underlying this phenomenon remains unclear. We hypothesized that age-related epigenetic alterations lead to decreased expression and functionality of the dopamine D2 receptor (D2R), contributing to this susceptibility. Methods In this study, we treated young (2–3 months old) and aged (22–24 months old) C57BL/6 mice with the D2R antagonist haloperidol (HAL) once a day for 14 days to evaluate HAL-induced motor side effects. In addition, we pretreated separate groups of young and aged mice with histone deacetylase (HDAC) inhibitors valproic acid (VPA) or entinostat (MS-275) and then administered HAL. Results Our results show that the motor side effects of HAL are exaggerated in aged mice as compared to young mice and that HDAC inhibitors are able to reverse the severity of these deficits. HAL-induced motor deficits in aged mice are associated with an age- and drug-dependent decrease in striatal D2R protein levels and functionality. Further, histone acetylation was reduced while histone trimethylation was increased at specific lysine residues of H3 and H4 within the Drd2 promoter in the striatum of aged mice. HDAC inhibitors, particularly VPA, restored striatal D2R protein levels and functionality and reversed age- and drug-related histone modifications at the Drd2 promoter. Conclusions These results suggest that epigenetic changes at the striatal Drd2 promoter drive age-related increases in antipsychotic side effect susceptibility, and HDAC inhibitors may be an effective adjunct treatment strategy to reduce side effects in aged populations.