Neuro-inflammatory processes that contribute to development of Alzheimer’s are evident early in the latent prodromal phase and worsen during the course of the disease. Despite substantial mechanistic and clinical evidence of inflammation, therapeutic approaches targeting inflammation have failed to alter the course of the disease. Disparate results from epidemiological and clinical trials targeting inflammation, highlight the complexity of the inflammatory process. Herein we review the dynamics of the inflammatory process across aging, midlife endocrine transitions, and the APOEε4 genotype and their contribution to progression of Alzheimer’s disease (AD). We discuss the chronic inflammatory processes that are activated during midlife chronological and endocrine aging, which ultimately limit the clearance capacity of microglia and lead to immune senescence. Aging, menopause, and APOEε4 combine the three hits of a compromised bioenergetic system of menopause with the chronic low grade innate inflammation of aging with the APOEε4 dyslipidemia and adaptive immune response. The inflammatory immune response is the unifying factor that bridges across each of the risk factors for AD. Immune system regulators that are specific to stage of disease and inflammatory phenotype would provide a therapeutic strategy to disconnect the bridge that drives disease. Outcomes of this analysis provide plausible mechanisms underlying failed clinical trials of anti-inflammatory agents in Alzheimer’s patients. Further, they highlight the need for stratifying AD clinical trial cohorts based on inflammatory phenotype. Combination therapies that include targeted use of anti-inflammatory agent’s specific to the immune phenotype are considered.

Decline in brain glucose metabolism is a hallmark of late-onset Alzheimer's disease (LoAD). comprehensive understanding of the dynamic metabolic aging process in brain can provide insights into windows of opportunities to promote healthy brain aging. chronological and endocrinological aging are associated with brain glucose hypometabolism and mitochondrial adaptations in female brain. Using a rat model recapitulating fundamental features of the human menopausal transition, results of transcriptomic analysis revealed stage-specific shifts in bioenergetic systems of biology that were paralleled by bioenergetic dysregulation in midlife aging female brain. Transcriptomic profiles were predictive of outcomes from unbiased, discovery-based metabolomic and lipidomic analyses, which revealed a dynamic adaptation of the aging female brain from glucose centric to utilization of auxiliary fuel sources that included amino acids, fatty acids, lipids, and ketone bodies. coupling between brain and peripheral metabolic systems was dynamic and shifted from uncoupled to coupled under metabolic stress. Collectively, these data provide a detailed profile across transcriptomic and metabolomic systems underlying bioenergetic function in brain and its relationship to peripheral metabolic responses. Mechanistically, these data provide insights into the complex dynamics of chronological and endocrinological bioenergetic aging in female brain. Translationally, these findings are predictive of initiation of the prodromal / preclinical phase of LoAD for women in midlife and highlight therapeutic windows of opportunity to reduce the risk of late-onset Alzheimer's disease. Late onset Alzheimer's disease (LOAD) is a complex disease with approximately a 20-year prodromal period 1-3. The prodromal/preclinical phase of AD is associated with brain glucose hypometabolism, which can be detected in at-risk-groups before diagnosis of the disease, and is predictive of disease progression 4-13. Brain glucose hypometabolism, mitochondrial dysfunction, and reduced oxygen flow in the brain are considered primary risk factors for LOAD 14-18. On the cellular level, aging is associated with reduced glucose transporter expression, compromised hexokinase activity, phosphorylated (inactivated) PDH, and altered levels and activities of key enzymes involved in oxidative phosphorylation 19-36. On the molecular level, aging is associated with significant down regulation of nuclear encoded OXPHOS genes 19,37 and disrupted balance of NAD/NADH, AMP/ ATP, purine and pyrimidine pool 38,39. During midlife, females experience both chronological and endocrinological aging. The perimenopausal to menopausal transition is unique to females, and is linked to deficits in brain glucose metabolism and mitochondrial dysfunction 3,19,40 , which could contribute to the twofold greater lifetime risk of AD in females 41-43. Under normal conditions, brain utilizes glucose as its primary fuel source. Under stress conditions, the brain can adapt to utilize auxiliary fuel sources in respon...

Previous studies have suggested that CD47, an essential cell-surface protein, plays an important role in polymorphonuclear neutrophil (PMN) transmigration across tissue cells and extracellular matrix. In the current study, the role of CD47 in PMN transmigration and infiltration into tissues was further evaluated by investigating the function of CD47−/− PMN and inflammatory conditions induced in CD47−/− mice. Using in vitro time-course assays, we found that CD47−/− PMN exhibited no impediment, but slightly enhanced response to and transmigration toward, the chemoattractant fMLF. In vivo analysis in CD47−/− mice by inducing acute peritonitis and aggressive colitis observed consistent results, indicating that both PMN and monocytes effectively infiltrated inflammatory sites despite the absence of CD47 on these leukocytes or the surrounding tissue cells. Although PMN transmigration was not delayed in CD47−/− mice, fewer PMN were found in the intestine at the postacute/chronic stage of chronic colitis induced with sustained low-dose dextran sulfate sodium. Further analysis suggested that the paucity of PMN accumulation was attributable to attenuated granulopoiesis secondary to assessed lower levels of IL-17. Administration of exogenous IL-17A markedly increased PMN availability and rapidly rendered severe colitis in CD47−/− mice under dextran sulfate sodium treatment.

Late onset Alzheimer's disease (LOAD) is a progressive neurodegenerative disease with four well-established risk factors: age, APOE4 genotype, female chromosomal sex, and maternal history of AD. Each risk factor impacts multiple systems, making LOAD a complex systems biology challenge. To investigate interactions between LOAD risk factors, we performed multiple scale analyses, including metabolomics, transcriptomics, brain magnetic resonance imaging (MRI), and beta-amyloid assessment, in 16 months old male and female mice with humanized human APOE3 (hAPOE3) or APOE4 (hAPOE4) genes. Metabolomic analyses indicated a sex difference in plasma profile whereas APOE genotype determined brain metabolic profile. Consistent with the brain metabolome, gene and pathway-based RNA-Seq analyses of the hippocampus indicated increased expression of fatty acid/lipid metabolism related genes and pathways in both hAPOE4 males and females. Further, female transcription of fatty acid and amino acids pathways were significantly different from males. MRI based imaging analyses indicated that in multiple white matter tracts, hAPOE4 males and females exhibited lower fractional anisotropy than their hAPOE3 counterparts, suggesting a lower level of white matter integrity in hAPOE4 mice. Consistent with the brain metabolomic and transcriptomic profile of hAPOE4 carriers, beta-amyloid generation was detectable in 16-month-old male and female brains. These data provide therapeutic targets based on chromosomal sex and APOE genotype. Collectively, these data provide a framework for developing precision medicine interventions during the prodromal phase of LOAD, when the potential to reverse, prevent and delay LOAD progression is greatest.

The brain undergoes two aging programs: chronological and endocrinological. This is particularly evident in the female brain, which undergoes programs of aging associated with reproductive competency. Comprehensive understanding of the dynamic metabolic and neuroinflammatory aging process in the female brain can illuminate windows of opportunities to promote healthy brain aging. Bioenergetic crisis and chronic low-grade inflammation are hallmarks of brain aging and menopause and have been implicated as a unifying factor causally connecting genetic risk factors for Alzheimer’s disease and other neurodegenerative diseases. In this review, we discuss metabolic phenotypes of pre-menopausal, peri-menopausal, and post-menopausal aging and their consequent impact on the neuroinflammatory profile during each transition state. A critical aspect of the aging process is the dynamic metabolic neuro-inflammatory profiles that emerge during chronological and endocrinological aging. These dynamic systems of biology are relevant to multiple age-associated neurodegenerative diseases and provide a therapeutic framework for prevention and delay of neurodegenerative diseases of aging. While these findings are based on investigations of the female brain, they have a broader fundamental systems of biology strategy for investigating the aging male brain. Molecular characterization of alterations in fuel utilization and neuroinflammatory mechanisms during these neuro-endocrine transition states can inform therapeutic strategies to mitigate the risk of Alzheimer’s disease in women. We further discuss a precision hormone replacement therapy approach to target symptom profiles during endocrine and chronological aging to reduce risk for age-related neurodegenerative diseases.

SIRPα, an ITIMs-containing signaling receptor, negatively regulates leukocyte responses through extracellular interactions with CD47. However, the dynamics of SIRPα-CD47 interactions on the cell surface and the governing mechanisms remain unclear. Here we report that while the purified SIRPα binds to CD47 and that SIRPα is expressed on monocytes and monocytic THP-1 or U937, these SIRPα are ineffective to mediate cell binding to immobilized CD47. However, cell binding to CD47 is significantly enhanced when monocytes transmigrating across endothelia, or being differentiated into macrophages. Cell surface labeling reveals SIRPα to be diffused on naïve monocytes but highly clustered on transmigrated monocytes and macrophages. Protein crosslink and equilibrium centrifugation confirm that SIRPα in the latter cells forms oligomerized complexes resulting in increased avidity for CD47 binding. Furthermore, formation of SIRPα complexes/clusters requires the plasma membrane ‘lipid rafts’ and the activity of Src family kinase during macrophage differentiation. These results together suggest that ‘clustering’ SIRPα into plasma membrane microdomains is essential for activated monocytes and macrophages to effectively interact with CD47 and initiate intracellular signaling.

Perimenopause marks initiation of female reproductive senescence with age-of-onset 47% heritable suggesting that factors other than inheritance regulate this endocrine aging transition. To elucidate these factors, we characterized transcriptional and epigenomic changes across endocrine aging transitions using a rat model recapitulating characteristics of human perimenopause. RNAseq analysis revealed that hypothalamic aging precedes perimenopause. In the hypothalamus, global DNA methylation declined with both age and reproductive senescence. Treatment with the DNA-methyltransferase-1 inhibitor accelerated transition to reproductive senescence, menopause, whereas supplementation with the S-adenosyl-methionine precursor methionine delayed onset of perimenopause and endocrine aging. Genome-wide epigenetic analysis revealed DNA methylation of genes required for hormone signaling, glutamate signaling, and melatonin and circadian pathways. Specific epigenetic changes in these signaling pathways provide insight into origin of perimenopause-associated neurological symptoms such as insomnia. Collectively, these data provide evidence that female neuroendocrine aging precedes ovarian failure and that DNA methylation regulates the onset and duration of perimenopause.

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