Chlamydia pneumoniae is an intracellular bacterium implicated in Alzheimer’s disease (AD), but its role in retinal pathology and disease progression is unclear. Here we identify Chlamydia pneumoniae inclusions in the retina, showing higher burden in AD retina and brain, increasing with APOEε4, disease stage, and cognitive deficit. Retinal and cortical proteomics reveal bacterial-infection and related NLRP3-inflammasome pathways. Retinal NLRP3 is elevated in mild cognitive impairment and activated in AD dementia, evidenced by increased caspase-1, cleaved interleukin-1β, and cleaved N-terminal gasdermin-D. Chlamydia pneumoniae associates with amyloid-β42, inflammation, apoptosis, pyroptosis, and AD status. In neuronal cultures and APPSWE/PS1ΔE9 model mice, infection induces amyloid-β, inflammasome activation, neuroinflammation, and neurotoxicity, and chronic infection worsens cognition. Fewer pathogen-colocalized microglia are found in AD retinas, implying impaired clearance. Machine learning detects retinal Chlamydia pneumoniae or NLRP3, combined with amyloid-β42, as predictors of AD diagnosis and stage. These findings support a disease-amplifying role for Chlamydia pneumoniae and propose NLRP3-attenuation or antibiotic-based early interventions. This study detects Chlamydia pneumoniae in human retina and brain, increasing with AD severity. Retinal pathogen load with Aβ42 may predict AD stage. In models, infection drives Aβ deposition and NLRP3 activation, worsening pathology and cognition.

Synaptic dysfunction is a major driver of cognitive decline in Alzheimer's disease (AD), yet its extent and molecular basis in the retina remain poorly defined. We integrated postmortem retinal and matched brain histopathology with ultrastructural, proteomic, biochemical, and machine-learning analyses across cognitively normal, mild cognitive impairment, and AD cohorts. Retinal glutamatergic synapses exhibited early, progressive degeneration, marked by loss of presynaptic vesicular glutamate transporter 1 (VGLUT1) and synaptophysin and postsynaptic density protein 95 (PSD95) and N-methyl-D-aspartate receptor subunit 2A (NMDAR2A), along with ribbon synapse ultrastructural disruption. Synaptic deficits correlated with amyloid-β42 (Aβ42), pathogenic tau, oxidative stress, the Aβ-binding p75 neurotrophin receptor, and glial activation that paralleled disease progression. Proteomics revealed widespread synaptic remodeling accompanied by disease-associated microglia, astrocyte-mediated excitotoxicity, and pyroptotic pathways. The synapse-enriched deubiquitinase ubiquitin C-terminal hydrolase L1 (UCHL1) was dysregulated early, particularly in horizontal and bipolar interneurons, and strongly associated with synaptic loss and neuroinflammation. Mechanistically, fibrillar Aβ42 induced rapid UCHL1 and synaptic depletion in human and murine neurons before overt neurodegeneration. Machine-learning models identified retinal UCHL1 as the strongest predictor of Braak stage and cognitive impairment. These findings establish the retina as an early site of AD synaptopathy and position UCHL1 as a candidate biomarker and mechanistic mediator linking amyloid pathology, neuroinflammation, and synaptic vulnerability.

Synaptic failure predicts cognitive decline in Alzheimer's disease (AD), yet its impact and molecular drivers in the human retina remain unclear. Leveraging the retina as an accessible central nervous system (CNS) proxy, we integrated spatially resolved histopathology of retinal cross-sections with ultrastructural, proteomic, and biochemical profiling across independent postmortem cohorts spanning normal cognition, mild cognitive impairment due to AD (MCI), and AD dementia. We uncover early, progressive degeneration of excitatory glutamatergic synapses, evidenced by losses of presynaptic vesicular glutamate transporter 1 (VGLUT1) and synaptophysin, and postsynaptic density protein 95 (PSD95) and N-methyl-D-aspartate receptor subunit 2A (NMDAR2A), accompanied by disruption of synaptic ultrastructure. Retinal synaptic loss tightly associates with local accumulation of amyloid-β 42 (Aβ42) and immature tau species, heightened oxidative stress, and upregulation of the Aβ-binding death receptor p75 neurotrophin receptor (p75NTR). Notably, the synapse-enriched deubiquitinase ubiquitin C-terminal hydrolase L1 (UCHL1) is profoundly dysregulated, correlates with synaptic integrity and cognition, and emerges as the strongest retinal predictor of Braak stage and cognitive status in multivariable machine-learning models. Together, these findings position retinal Aβ/p75NTR-mediated UCHL1 imbalance as a proteostasis-synapse mechanistic hub and candidate biomarker reflecting AD severity.

Epigenetic dysregulation is increasingly linked to ageing and neurodegeneration, yet its contribution to retinal and brain pathology in Alzheimer's disease (AD) remains uncharacterized. We quantified the repressive histone mark H3K9me3 in post-mortem retinas and brains from donors spanning normal cognition, mild cognitive impairment, and AD dementia. In both tissues, H3K9me3 increased in early stages and further in AD dementia, strongly associating with cognitive status and neuropathological burden. To assess causality, we inhibited the H3K9 methyltransferase SUV39H1 in APPswe/PS1dE9 and APPswe/tauP301L/PS1tm1Mpm mouse models. SUV39H1 inhibition lowered H3K9me3, mitigated AD-like pathology, restored synaptic integrity, and improved cognitive and visual performance. Proteomics revealed that H3K9me3 derepression reestablished retinal and brain proteostasis and promoted neuroprotection through immunomodulatory pathways and BDNF/VGF–granin signalling. These findings identify H3K9me3 as shared epigenetic driver of AD-related dysfunction, highlight H3K9me3 reduction as therapeutic strategy, and position the retina as an accessible extension of the brain for epigenetic studies.

Women face a twofold higher lifetime risk of Alzheimer's disease (AD) than men, yet the mechanisms underlying female-biased vulnerability and sex-specific disease signatures across the retina-brain axis remain unknown. By integrating clinicopathological and proteomic datasets from paired retinal and brain tissues from 182 donors, we identified sex-divergent molecular and pathological features across the AD continuum. Despite comparable retinal and cerebral amyloid and tau burdens between sexes, females exhibited a more severe neuroinflammatory-neurodegenerative phenotype with intensified gliosis and tissue atrophy, whereas males displayed a dominant vasculopathy, marked by increased retinal vascular Aβ40 deposition, tight-junction disruption, and cerebral amyloid angiopathy. In females, this profile coincided with inflammation-associated estrogen receptor (ER)-α remodeling and reduced global and astrocytic-nuclear ER-β, which associated more strongly with cognitive decline than in males. These results indicate that comparable AD proteinopathy is associated with divergent downstream consequences across the retina-brain axis and identify astrocytic ERα/ERβ imbalance as a sex-linked glial mechanism associated with female vulnerability in AD.

Alzheimer’s disease (AD) is a progressive irreversible dementia characterized by beta-amyloid protein plaque deposition and hyperphosphorylation of tau forming neurofibrillary tangles, and neurodegeneration. An emerging theory posits that infections could be one of the triggering factors in AD development and progression. Multiple lines of evidence have linked Chlamydia pneumoniae (Cp), a gram-negative obligate intracellular bacterium with AD. Cp has been detected in the post-mortem brain tissues of AD patients, however, pathomechanisms associated with Cp in AD remain unknown. Transgenic APP SWE /PS1 ∆E9 (ADtg) mice and non-tg wildtype (WT) littermates were infected with Cp intranasally and sacrificed either 1 week or 6 months after infection. Mice were perfused with saline, and the brains were harvested for subsequent analysis, including PCR, flow cytometry, immunofluorescence, and live Cp growth. Neurobehavioral functions were assessed through an open field, visual-stimuli X maze, and Barnes maze tests. Primary microglia and astrocytes were infected with Cp and cytokine and chemokines production was measured by ELISA. We found Cp in the olfactory bulb and brain of mice 7 days after infection and the infiltration of inflammatory cells into the brain. Cp infection resulted in microglial activation. Immunohistochemical analysis also revealed the activation of microglia and astrocytes in the Cp-infected mouse brain. In addition, Cp infection led to increased mRNA expression of neuroinflammatory mediators such as cytokines and chemokines. Primary astrocytes and microglia cultures could sustain Cp growth and produce proinflammatory cytokines and chemokines in response to infection. Live Cp in the brain was also observed 7 months after infection and the Cp load was higher in ADtg mice than WT. Cp infection resulted in significant cognitive decline in both WT as well as ADtg mice together with increased AD-related neuropathology. Intranasal Cp infection leads to brain colonization and altered Iba1 immunoreactivity. Both primary astrocytes and microglia support Cp growth and produce neuroinflammatory cytokines. Long-term Cp infection promotes neuroinflammation and cognitive decline in mice along with increased Aβ deposits. Cognitive impairment in Cp-infected ADtg and WT mice as well as increased Aβ in ADtg mice suggest that Cp infection may play an important pathological role in AD development.

Emerging evidence implicates bacterial infections, including Chlamydia pneumoniae (Cp), a gram-negative obligate intracellular bacterium responsible for community-acquired pneumonia, in Alzheimer's disease (AD) pathogenesis. However, the involvement of Cp in early and advanced AD in the retina is unknown. Here, we identified the existence and distribution of intracellular Cp inclusions and related NLRP3 inflammasome activation and neurodegeneration in postmortem retinas and brains from 95 human donors. Histological analysis in neuropathologically-confirmed MCI and AD patients compared with cognitively normal individuals (n=70), revealed 2.9-4.1-fold increases of Cp inclusions in AD retinas and brains, respectively, with no significant increases in MCI retinas or brains. Mass spectrometry-based proteomics in additional cohorts (n=30), revealed dysregulated brain and retinal bacterial infection-related proteins and inflammasome-associated pathways. Retinal Cp was strongly linked to Aβ42, caspase-1 and NLRP3-inflammasome activation components, as well as cleaved caspase-3+ apoptosis and cleaved gasdermin D pyroptotic cell death. Despite increased IBA1+ microgliosis in the AD retina, the Cp-associated microglial population was reduced by 62%, suggesting impaired microglial phagocytosis. Higher retinal Cp burden correlated with APOEε4 status, advanced Braak stage, and cognitive decline. Machine learning models revealed that retinal Cp or NLRP3, in combination with retinal Aβ42, effectively predicted AD diagnosis, Braak stage, and cognition. These findings suggest that Cp infection contributes to AD dementia but is unlikely to initiate AD pathological changes, whereas elevated retinal NLRP3 may serve as an early AD marker. These results underscore the need for future studies investigating Cp's role in AD dementia and testing early antibiotic or inflammasome-targeting therapies.

Alzheimer's disease (AD) pathology extends beyond the brain to the neurosensory retina. Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), a key enzyme in the ubiquitin-proteasome system, has a synaptic protective function and was recently implicated in amyloid β-protein (Aβ) plaque accumulation in AD brains. However, its expression in the retina and potential relationship with synaptic and cognitive integrity remain unexplored. We used immunohistochemistry and mass spectrometry to assess pre- and post-synaptic markers alongside UCH-L1 expression in postmortem retinas from AD and mild cognitive impairment (MCI) patients, comparing them to age- and sex-matched cognitively normal controls (NC). Data were correlated with AD-related brain pathology staging (Braak, ABC scores) and cognitive function (MMSE, CDR scores). An integrated, AI-based multi-variable Random Forest analysis identified key predictors of disease status. MCI and AD patients showed significant retinal synaptic loss in both inner (IPL) and outer (OPL) plexiform layers, with pre-synaptic markers (VGLUT1: 44%-59%, Synaptophysin: 56%-77%) and post-synaptic markers (PSD95: 44%-66%, NMDAR2B: 59%-74%) markers markedly reduced. Membrane-associated UCH-L1 (M) levels decreased by 43%-69% across retinal layers. These reductions strongly correlated with retinal Aβ 42 and phosphorylated tau (pS396, p  <0.0001) and were closely linked with cognitive dysfunction, higher Braak stage, and ABC scores. Our findings reveal early and substantial synaptic loss and UCH-L1 M decline in MCI and AD retinas, closely associated with Aβ-induced p75NTR-mediated cell death. Random Forest analysis identified UCH-L1 M as a top predictor of brain tauopathy progression (Braak stage) and cognitive impairment (MMSE), highlighting its potential as both a retinal biomarker for AD detection and a therapeutic target.

Chlamydia pneumoniae (Cp), an obligate intracellular bacterium, has been implicated in Alzheimer's disease (AD), yet its role in retinal pathology remains unexplored. We analyzed postmortem tissues from 95 human donors and found 2.9-4.1-fold increases in Cp inclusions in AD retinas and brains, with no significant elevation in mild cognitive impairment (MCI). Proteomics revealed dysregulation of retinal and brain bacterial infection-related proteins and NLRP3 inflammasome pathways. NLRP3 expression was markedly elevated in MCI and AD retinas, and its activation was evident by increased N-terminal gasdermin D (NGSDMD) and mature interleukin-1β. Retinal Cp strongly correlated with Aβ42 and NLRP3 inflammasome components, which tightly linked to cleaved caspase-3-apoptotic and NGSDMD-pyroptotic cell death. Although retinal microgliosis was elevated in AD, Cp-associated microglia were reduced by 62%, suggesting impaired Cp phagocytosis. Higher retinal Cp burden correlated with APOEε4, Braak stage, and cognitive deficit. Machine learning identified retinal Cp or NLRP3 combined with Aβ42 as strong predictors of AD diagnosis, staging, and cognitive impairment. Our findings suggest that Cp infection contributes to AD dementia but not initiating pathology, whereas early NLRP3 activation may promote disease development, warranting studies on Cp's role in AD pathogenesis and early antibiotic or inflammasome-targeted therapies.

Alzheimer’s disease (AD) is the foremost cause of global dementia, also characterized by retinal changes involving Aβ, hyperphosphorylated-tau (p-tau), neuronal degeneration, and tissue atrophy. Mitochondrial-driven reactive oxygen species (ROS) production, linked to synaptic dysfunction, is common to various neurodegenerative conditions, including AD. Despite synaptic dysfunction being an early predictor of cognitive decline in AD, its occurrence in the AD retina is unexplored. This study examines retinal neurodegeneration and synaptic integrity in correlation with AD brain and retinal pathology. Utilizing histological and mass spectrometry approaches, we assessed atrophy, early apoptosis, cell death markers, ROS levels and pre- and post-synaptic markers in post-mortem retinas from confirmed AD and mild cognitively impairment (MCI) patients compared to age- and sex-matched subjects with normal cognition (NC). We applied Pearson’s ( r ) correlation analyses to determine the relationships between retinal tauopathy, amyloidosis, gliosis, ROS, apoptosis, and tissue atrophy severity, and their association with synaptic biomarkers. These retinal observations were then correlated with AD-related brain parameters and cognitive scores. Proteomics analysis in AD patients’ retinas revealed a strong link between synaptic loss and neurodegeneration. In MCI and AD, we detected highly significant neurodegeneration (Nissl staining) in the outer nuclear layer (ONL; 28%; 23%), inner nuclear layer (INL; 38%; 21%), and ganglion cell layer (GCL; 54%; 52%), accompanied by increased ROS levels (1.9; 2.2-fold; by DHE staining) respectively, compared to NC. Marked pre- (Synaptophysin: 56%; 77%) and post- (PSD95: 44%; 66%) synaptic losses were detected in the inner and outer plexiform layers of MCI and AD patients, along with strong negative correlations with accumulation of retinal pSer396-tau, Aβ 42 and gliosis. The retinas of these patients also exhibited significant increases in early apoptotic markers. Remarkably, retinal synaptic loss and neurodegeneration had a strong negative correlation with severity of cognitive impairment, BRAAK stage, and ABC score. Our study reveals pronounced retinal neurodegeneration at pSer396-tau and Aβ 42 accumulation sites, coupled with increased retinal oxidative stress in MCI and AD patients. Elevated retinal ROS and pre-apoptotic cells may contribute to synaptic loss and neuronal death. These findings suggest that retinal synaptic loss and neurodegeneration may predict AD status.

Background Delirium affects 50-85% of patients on mechanical ventilation and is associated with increased mortality, prolonged hospitalization, and a three-fold higher risk of dementia. Microglia, the resident immune cells of the brain, exhibit both neuroprotective and neurotoxic functions; however, their effects in mechanical ventilation-induced acute lung injury (VILI) are unknown. We hypothesize that in a model of short-term VILI, microglia play a neuroprotective role to ameliorate delirium-like phenotypes. Methods Microglia depletion (n = 18) was accomplished using an orally administered colony stimulating factor 1 receptor inhibitor, while controls received a vehicle diet (n = 18). We then compared extent of neuronal injury in the frontal cortex and hippocampus using cleaved caspase-3 (CC3) and multiple delirium-like behaviors in microglia depleted and non-microglia depleted male mice (C57BL/6 J aged 4-9 months) following VILI. Delirium-like behaviors were evaluated using the Open Field, Elevated Plus Maze, and Y-maze assays. We subsequently evaluated whether repopulation of microglia (n = 14 repopulation, 14 vehicle) restored the phenotypes. Results Frontal/hippocampal neuronal CC3 levels were significantly higher in microglia depleted VILI mice compared to vehicle-treated VILI controls (p < 0.01, p < 0.01, respectively). These structural changes were accompanied by worse delirium-like behaviors in microglia depleted VILI mice compared to vehicle controls. Specifically, microglia depleted VILI mice demonstrated: (1) significantly increased time in the periphery of the Open Field (p = 0.01), (2) significantly increased coefficient of variation (p = 0.02), (3) trend towards reduced time in the open arms of the Elevated Plus Maze (p = 0.09), and (4) significantly decreased spontaneous alternations on Y-maze (p < 0.01). There was a significant inverse correlation between frontal CC3 and percent spontaneous alternations (R2 = 0.51, p < 0.01). Microglia repopulation showed a near-complete return to vehicle levels of delirium like-behaviors. Conclusions This study demonstrates that microglia depletion exacerbates structural and functional delirium-like phenotypes after VILI, while subsequent repopulation of microglia restores these phenotypes. These findings suggest a neuroprotective role for microglia in ameliorating neuronal and functional delirium-like phenotypes and call for consideration of interventions that leverage endogenous microglia physiology to mitigate delirium.

We investigated the role of histone 3 lysine 9 trimethylation (H3K9me3), an epigenetic mechanism involved in the repression of synaptic plasticity and memory-related genes, within aging and Alzheimer's disease (AD). Our study reveals that elevated cortical H3K9me3 strongly correlates with cognitive dysfunction in individuals with mild cognitive impairment (MCI) and AD. In old (18 months) and younger (14 months) APPSWE/PS1ΔE9 and 3xTg AD mouse models, inhibiting SUV39H1 methyltransferase with ETP69, substantially reduces cerebral H3K9me3 levels and attenuates amyloid-β burden, tau pathology, and gliosis. Administration of ETP69 further promotes dendritic spine formation, leading to rapid and sustained improvements in cognitive function. Proteomics analysis indicates that a significant proportion of dysregulated proteins in the brains of AD-model mice are reversed by ETP69. These proteins are enriched for synaptic plasticity and learning-related pathways. ETP69 exerts its effects through multiple neuroprotective mechanisms, including regulation of neuroinflammation, induction of both blood and cerebral-infiltrating monocytes involved in cerebral Aβ clearance. Moreover, ETP69 activates brain-derived neurotrophic factor (Bdnf) network, and particularly its downstream effector neurosecretory protein Vgf. These findings support the pharmacological inhibition of H3K9me3-mediated gene silencing to reverse AD-related pathology and cognitive decline. ### Competing Interest Statement KLB is the CEO and shareholder of Fortem Neurosciences, Inc. KLB and MKH are inventors of a related patent Compositions and methods for treating Alzheimer's disease (PCT/US2021/044195). The other authors have no conflicts to disclose.

The retina is an emerging CNS target for potential noninvasive diagnosis and tracking of Alzheimer's disease (AD). Studies have identified the pathological hallmarks of AD, including amyloid β-protein (Aβ) deposits and abnormal tau protein isoforms, in the retinas of AD patients and animal models. Moreover, structural and functional vascular abnormalities such as reduced blood flow, vascular Aβ deposition, and blood-retinal barrier damage, along with inflammation and neurodegeneration, have been described in retinas of patients with mild cognitive impairment and AD dementia. Histological, biochemical, and clinical studies have demonstrated that the nature and severity of AD pathologies in the retina and brain correspond. Proteomics analysis revealed a similar pattern of dysregulated proteins and biological pathways in the retina and brain of AD patients, with enhanced inflammatory and neurodegenerative processes, impaired oxidative-phosphorylation, and mitochondrial dysfunction. Notably, investigational imaging technologies can now detect AD-specific amyloid deposits, as well as vasculopathy and neurodegeneration in the retina of living AD patients, suggesting alterations at different disease stages and links to brain pathology. Current and exploratory ophthalmic imaging modalities, such as optical coherence tomography (OCT), OCT-angiography, confocal scanning laser ophthalmoscopy, and hyperspectral imaging, may offer promise in the clinical assessment of AD. However, further research is needed to deepen our understanding of AD's impact on the retina and its progression. To advance this field, future studies require replication in larger and diverse cohorts with confirmed AD biomarkers and standardized retinal imaging techniques. This will validate potential retinal biomarkers for AD, aiding in early screening and monitoring.

Background: Allan-Herndon-Dudley syndrome (AHDS) is a severe psychomotor disability disorder that also manifests characteristic abnormal thyroid hormone (TH) levels. AHDS is caused by inactivating mutations in monocarboxylate transporter 8 (MCT8), a specific TH plasma membrane transporter widely expressed in the central nervous system (CNS). MCT8 mutations cause impaired transport of TH across brain barriers, leading to insufficient neural TH supply. There is currently no successful therapy for the neurological symptoms. Earlier work has shown that intravenous (IV), but not intracerebroventricular adeno-associated virus serotype 9 (AAV9) -based gene therapy given to newborn Mct8 knockout (Mct8-/y) male mice increased triiodothyronine (T3) brain content and partially rescued TH-dependent gene expression, suggesting a promising approach to treat this neurological disorder. Methods: The potential of IV delivery of AAV9 carrying human MCT8 was tested in the well-established Mct8-/y/Organic anion-transporting polypeptide 1c1 (Oatp1c1)-/ - double knockout (dKO) mouse model of AHDS, which, unlike Mct8-/y mice, displays both neurological and TH phenotype. Further, as the condition is usually diagnosed during childhood, treatment was given intravenously to P30 mice and psychomotor tests were carried out blindly at P120-P140 after which tissues were collected and analyzed. Results: Systemic IV delivery of AAV9-MCT8 at a juvenile stage led to improved locomotor and cognitive functions at P120-P140, which was accompanied by a near normalization of T3 content and an increased response of positively regulated TH-dependent gene expression in different brain regions examined (thalamus, hippocampus, and parietal cortex). The effects on serum TH concentrations and peripheral tissues were less pronounced, showing only improvement in the serum T3/reverse T3 (rT3) ratio and in liver deiodinase 1 expression. Conclusion: IV administration of AAV9, carrying the human MCT8, to juvenile dKO mice manifesting AHDS has long-term beneficial effects, predominantly on the CNS. This preclinical study indicates that this gene therapy has the potential to ameliorate the devastating neurological symptoms in patients with AHDS.

Dopaminergic neuron degeneration in the midbrain plays a pivotal role in motor symptoms associated with Parkinson’s disease. However, non-motor symptoms of Parkinson’s disease and post-mortem histopathology confirm dysfunction in other brain areas, including the locus coeruleus and its associated neurotransmitter norepinephrine. Here, we investigate the role of central norepinephrine-producing neurons in Parkinson’s disease by chronically stimulating catecholaminergic neurons in the locus coeruleus using chemogenetic manipulation. We show that norepinephrine neurons send complex axonal projections to the dopaminergic neurons in the substantia nigra, confirming physical communication between these regions. Furthermore, we demonstrate that increased activity of norepinephrine neurons is protective against dopaminergic neuronal depletion in human α-syn A53T missense mutation over-expressing mice and prevents motor dysfunction in these mice. Remarkably, elevated norepinephrine neurons action fails to alleviate α-synuclein aggregation and microgliosis in the substantia nigra suggesting the presence of an alternate neuroprotective mechanism. The beneficial effects of high norepinephrine neuron activity might be attributed to the action of norepinephrine on dopaminergic neurons, as recombinant norepinephrine treatment increased primary dopaminergic neuron cultures survival and neurite sprouting. Collectively, our results suggest a neuroprotective mechanism where noradrenergic neurons activity preserves the integrity of dopaminergic neurons, which prevents synucleinopathy-dependent loss of these cells.

Urinary tract infections (UTIs) are common and frequently precipitate delirium-like states. Advanced age coincident with the postmenopausal period is a risk factor for delirium following UTIs. We previously demonstrated a pathological role for interleukin-6 (IL-6) in mediating delirium-like phenotypes in a murine model of UTI. Estrogen has been implicated in reducing peripheral IL-6 expression, but it is unknown whether the increased susceptibility of postmenopausal females to developing delirium concomitant with UTIs reflects diminished effects of circulating estrogen. Here, we tested this hypothesis in a mouse model of UTI. Female C57BL/6J mice were oophorectomized, UTIs induced by transurethral inoculation of E. coli , and treated with 17β-estradiol. Delirium-like behaviors were evaluated prior to and following UTI and 17β-estradiol treatment. Compared to controls, mice treated with 17β-estradiol had less neuronal injury, improved delirium-like behaviors, and less plasma and frontal cortex IL-6. In vitro studies further showed that 17β-estradiol may also directly mediate neuronal protection, suggesting pleiotropic mechanisms of 17β-estradiol-mediated neuroprotection. In summary, we demonstrate a beneficial role for 17β-estradiol in ameliorating acute UTI-induced structural and functional delirium-like phenotypes. These findings provide pre-clinical justification for 17β-estradiol as a therapeutic target to ameliorate delirium following UTI.

We introduce a novel visual-stimuli four-arm maze (ViS4M) equipped with spectrally- and intensity-controlled LED emitters and dynamic grayscale objects that relies on innate exploratory behavior to assess color and contrast vision in mice. Its application to detect visual impairments during normal aging and over the course of Alzheimer’s disease (AD) is evaluated in wild-type (WT) and transgenic APPSWE/PS1∆E9 murine models of AD (AD+) across an array of irradiance, chromaticity, and contrast conditions. Substantial color and contrast-mode alternation deficits appear in AD+ mice at an age when hippocampal-based memory and learning is still intact. Profiling of timespan, entries and transition patterns between the different arms uncovers variable AD-associated impairments in contrast sensitivity and color discrimination, reminiscent of tritanomalous defects documented in AD patients. Transition deficits are found in aged WT mice in the absence of alternation decline. Overall, ViS4M is a versatile, controlled device to measure color and contrast-related vision in aged and diseased mice.