Dynamic transcriptomic responses to divergent acute exercise stimuli in young adults.

Acute exercise elicits dynamic transcriptional changes that, when repeated, form the fundamental basis of health, resilience, and performance adaptations. While moderate-intensity endurance training combined with conventional resistance training (traditional, TRAD) is often prescribed and recommended by public health guidance, high-intensity training combining maximal-effort intervals with intensive, limited-rest resistance training is a time-efficient alternative that may be used tactically (HITT) to confer similar benefits. Mechanisms of action of these distinct stimuli are incompletely characterized and have not been directly compared. We assessed transcriptome-wide responses in skeletal muscle and circulating extracellular vesicles (EVs) to a single exercise bout in young adults randomized to TRAD (n = 21, 12 M/9 F, 22 ± 3 yr) or HITT (n = 19, 11 M/8 F, 22 ± 2 yr). Next-generation sequencing captured small, long, and circular RNA in muscle and EVs. Analysis identified differentially expressed transcripts (|log2FC|>1, FDR ≤ 0.05) immediately (h0, EVs only), h3, and h24 postexercise within and between exercise protocols. In aaddition, all apparently responsive transcripts (FDR < 0.2) underwent singular value decomposition to summarize data structures into latent variables (LVs) to deconvolve molecular expression circuits and interregulatory relationships. LVs were compared across time and exercise protocol. TRAD, a longer but less intense stimulus, generally elicited a stronger transcriptional response than HITT, but considerable overlap and key differences existed. Findings reveal shared and unique molecular responses to the exercise stimuli and lay groundwork toward establishing relationships between protein-coding genes and lesser-understood transcripts that serve regulatory roles following exercise. Future work should advance the understanding of these circuits and whether they repeat in other populations or following other types of exercise/stress.NEW & NOTEWORTHY We examined small and long transcriptomics in skeletal muscle and serum-derived extracellular vesicles before and after a single exposure to traditional combined exercise (TRAD) and high-intensity tactical training (HITT). Across 40 young adults, we found more consistent protein-coding gene responses to TRAD, whereas HITT elicited differential expression of microRNA enriched in brain regions. Follow-up analysis revealed relationships and temporal dynamics across transcript networks, highlighting potential avenues for research into mechanisms of exercise response and adaptation.

Longitudinal Assessment of Intravoxel Incoherent Motion Diffusion-Weighted MRI Metrics in Cognitive Decline.

BACKGROUND: Advanced diffusion-based MRI biomarkers may provide insight into microstructural and perfusion changes associated with neurodegeneration and cognitive decline. PURPOSE: To assess longitudinal microstructural and perfusion changes using apparent diffusion coefficient (ADC) and intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) parameters in cognitively impaired (CI) and healthy control (HC) groups. STUDY TYPE: Prospective/longitudinal. POPULATION: Twelve CI patients (75% female) and 13 HC subjects (69% female). FIELD STRENGTH/SEQUENCE: 3 T; Spin-Echo-IVIM-DWI. ASSESSMENT: Two MRI scans were performed with a 12-month interval. ADC and IVIM-DWI metrics (diffusion coefficient [D] and perfusion fraction [f]) were generated from monoexponential and biexponential fits, respectively. Additionally, voxel-based correlations were evaluated between change in Montreal Cognitive Assessment (ΔMoCA) and baseline imaging parameters. STATISTICAL TESTS: Analysis of covariance with sex and age as covariates was performed for main effects of group and time (false discovery rate [FDR] corrected) with post hoc comparisons using Bonferroni correction. Partial-η2 and Hedges' g were used for effect-size analysis. Spearman's correlations (FDR corrected) were used for the relationship between ΔMoCA score and imaging. P < 0.05 was considered statistically significant. RESULTS: Significant differences were found for the main effects of group (HC vs. CI) and time. For group effects, higher ADC, IVIM-D, and IVIM-f were observed in the CI group compared to HC (ADC: 1.23 ± 0.08. 10-3 vs. 1.09 ± 0.07. 10-3  mm2 /sec; IVIM-D: 0.82 ± 0.01. 10-3 vs. 0.73 ± 0.01. 10-3  mm2 /sec; and IVIM-f: 0.317 ± 0.008 vs. 0.253 ± 0.009). Significantly higher ADC, IVIM-D, and IVIM-f values were observed in the CI group after 12 months (ADC: 1.45 ± 0.05. 10-3 vs. 1.50 ± 0.07. 10-3  mm2 /sec; IVIM-D: 0.87 ± 0.01. 10-3 vs. 0.94 ± 0.02. 10-3  mm2 /sec; and IVIM-f: 0.303 ± 0.007 vs. 0.332 ± 0.008), but not in the HC group at large effect size. ADC, IVIM-D, and IVIM-f negatively correlated with ΔMoCA score (ρ = -0.49, -0.51, and -0.50, respectively). DATA CONCLUSION: These findings demonstrate that longitudinal differences between CI and HC cohorts can be measured using IVIM-based metrics. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.

MOBP and HIP1 in multiple system atrophy: New α-synuclein partners in glial cytoplasmic inclusions implicated in the disease pathogenesis.

AIMS: Multiple system atrophy (MSA) is a fatal neurodegenerative disease. Similar to Parkinson's disease (PD), MSA is an α-synucleinopathy, and its pathological hallmark consists of glial cytoplasmic inclusions (GCIs) containing α-synuclein (SNCA) in oligodendrocytes. We previously identified consistent changes in myelin-associated oligodendrocyte basic protein (MOBP) and huntingtin interacting protein 1 (HIP1) DNA methylation status in MSA. We hypothesized that if differential DNA methylation at these loci is mechanistically relevant for MSA, it should have downstream consequences on gene regulation. METHODS: We investigated the relationship between MOBP and HIP1 DNA methylation and mRNA levels in cerebellar white matter from MSA and healthy controls. Additionally, we analysed protein expression using western blotting, immunohistochemistry and proximity ligation assays. RESULTS: We found decreased MOBP mRNA levels significantly correlated with increased DNA methylation in MSA. For HIP1, we found a distinct relationship between DNA methylation and gene expression levels in MSA compared to healthy controls, suggesting this locus may be subjected to epigenetic remodelling in MSA. Although soluble protein levels for MOBP and HIP1 in cerebellar white matter were not significantly different between MSA cases and controls, we found striking differences between MSA and other neurodegenerative diseases, including PD and Huntington's disease. We also found that MOBP and HIP1 are mislocalized into the GCIs in MSA, where they appear to interact with SNCA. CONCLUSIONS: This study supports a role for DNA methylation in downregulation of MOBP mRNA in MSA. Most importantly, the identification of MOBP and HIP1 as new constituents of GCIs emphasizes the relevance of these two loci to the pathogenesis of MSA.

Molecular biomarkers to track clinical improvement following an integrative treatment model in autistic toddlers.

OBJECTIVES: Identifying an objective, laboratory-based diagnostic tool (e.g. changes in gene expression), when used in conjunction with disease-specific clinical assessment, could increase the accuracy of the effectiveness of a therapeutic intervention. METHODS: We assessed the association between treatment outcome and blood RNA expression before the therapeutic intervention to post-treatment (after 1 year) of five autism spectrum disorder (ASD) toddlers who underwent an intensive cognitive-behavioural intervention integrated with psychomotor and speech therapy. RESULTS: We found 113 significant differentially expressed genes enriched for the nervous system, immune system, and transcription and translation-related pathways. Some of these genes, as MALAT-1, TSPO, and CFL1, appear to be promising candidates. CONCLUSIONS: Our findings show that changes in peripheral gene expression could be used in conjunction with clinical scales to monitor a rehabilitation intervention's effectiveness in toddlers affected by ASD. These results need to be validated in a larger cohort.

Big data collision: the internet of things, wearable devices and genomics in the study of neurological traits and disease.

Advances in information technology (IT) hardware in the last decade have led to the advent of small connected devices broadly referred to as the Internet of Things (IoT). The IoT and its subcategory of wearable devices (wearables) both have the potential to greatly impact biomedical research. This focused review covers recent biomedical research using the IoT and wearables in the area of neurological traits and disease. In addition, a look into the future of biomedical research using IoT devices and wearables as well as some areas requiring further consideration by the field will be discussed.

Reducing Ribosomal Protein S6 Kinase 1 Expression Improves Spatial Memory and Synaptic Plasticity in a Mouse Model of Alzheimer's Disease.

Aging is the most important risk factor associated with Alzheimer's disease (AD); however, the molecular mechanisms linking aging to AD remain unclear. Suppression of the ribosomal protein S6 kinase 1 (S6K1) increases healthspan and lifespan in several organisms, from nematodes to mammals. Here we show that S6K1 expression is upregulated in the brains of AD patients. Using a mouse model of AD, we found that genetic reduction of S6K1 improved synaptic plasticity and spatial memory deficits, and reduced the accumulation of amyloid-ß and tau, the two neuropathological hallmarks of AD. Mechanistically, these changes were linked to reduced translation of tau and the ß-site amyloid precursor protein cleaving enzyme 1, a key enzyme in the generation of amyloid-ß. Our results implicate S6K1 dysregulation as a previously unidentified molecular mechanism underlying synaptic and memory deficits in AD. These findings further suggest that therapeutic manipulation of S6K1 could be a valid approach to mitigate AD pathology. SIGNIFICANCE STATEMENT: Aging is the most important risk factor for Alzheimer's disease (AD). However, little is known about how it contributes to AD pathogenesis. S6 kinase 1 (S6K1) is a protein kinase involved in regulation of protein translation. Reducing S6K1 activity increases lifespan and healthspan. We report the novel finding that reducing S6K1 activity in 3xTg-AD mice ameliorates synaptic and cognitive deficits. These improvement were associated with a reduction in amyloid-ß and tau pathology. Mechanistically, lowering S6K1 levels reduced translation of ß-site amyloid precursor protein cleaving enzyme 1 and tau, two key proteins involved in AD pathogenesis. These data suggest that S6K1 may represent a molecular link between aging and AD. Given that aging is the most important risk factor for most neurodegenerative diseases, our results may have far-reaching implications into other diseases.

Clade C HIV-1 isolates circulating in Southern Africa exhibit a greater frequency of dicysteine motif-containing Tat variants than those in Southeast Asia and cause increased neurovirulence.

BACKGROUND: HIV-1 Clade C (Subtype C; HIV-1C) is responsible for greater than 50% of infections worldwide. Unlike clade B HIV-1 (Subtype B; HIV-1B), which is known to cause HIV associated dementia (HAD) in approximately 15% to 30% of the infected individuals, HIV-1C has been linked with lower prevalence of HAD (0 to 6%) in India and Ethiopia. However, recent studies report a higher prevalence of HAD in South Africa, Zambia and Botswana, where HIV-1C infections predominate. Therefore, we examined whether Southern African HIV-1C is genetically distinct and investigated its neurovirulence. HIV-1 Tat protein is a viral determinant of neurocognitive dysfunction. Therefore, we focused our study on the variations seen in tat gene and its contribution to HIV associated neuropathogenesis. RESULTS: A phylogenetic analysis of tat sequences of Southern African (South Africa and Zambia) HIV isolates with those from the geographically distant Southeast Asian (India and Bangladesh) isolates revealed that Southern African tat sequences are distinct from Southeast Asian isolates. The proportion of HIV - 1C variants with an intact dicysteine motif in Tat protein (C30C31) was significantly higher in the Southern African countries compared to Southeast Asia and broadly paralleled the high incidence of HAD in these countries. Neuropathogenic potential of a Southern African HIV-1C isolate (from Zambia; HIV-1C 1084i), a HIV-1C isolate (HIV-1 IndieC1) from Southeast Asia and a HIV-1B isolate (HIV-1 ADA) from the US were tested using in vitro assays to measure neurovirulence and a SCID mouse HIV encephalitis model to measure cognitive deficits. In vitro assays revealed that the Southern African isolate, HIV-1C 1084i exhibited increased monocyte chemotaxis and greater neurotoxicity compared to Southeast Asian HIV-1C. In neurocognitive tests, SCID mice injected with MDM infected with Southern African HIV-1C 1084i showed greater cognitive dysfunction similar to HIV-1B but much higher than those exposed to Southeast Asian HIV - 1C. CONCLUSIONS: We report here, for the first time, that HIV-1C from Southern African countries is genetically distinct from Southeast Asian HIV-1C and that it exhibits a high frequency of variants with dicysteine motif in a key neurotoxic HIV protein, Tat. Our results indicate that Tat dicysteine motif determines neurovirulence. If confirmed in population studies, it may be possible to predict neurocognitive outcomes of individuals infected with HIV-1C by genotyping Tat.

Continuous estrone treatment impairs spatial memory and does not impact number of basal forebrain cholinergic neurons in the surgically menopausal middle-aged rat.

CEE (conjugated equine estrogens) is the most widely prescribed estrogen-only menopausal hormone therapy in the United States, and is comprised of over 50% estrone (E1) sulfate. Following CEE administration, E1 is the principal circulating estrogen. However, the cognitive and neurobiological effects of E1 in a middle-aged rodent model have not yet been evaluated. We assessed cognitive effects of continuous E1 treatment in middle-aged surgically menopausal rats using a maze battery. We also quantified number of choline acetyltransferase-immunoreactive (ChAT-IR) neurons in distinct basal forebrain regions known in earlier studies in to be impacted by the most potent naturally-circulating estrogen in rodents and women, 17ß-estradiol (17ß-E2), as well as CEE. On the spatial working memory delayed-match-to-sample water maze, the highest E1 dose impaired memory performance during acquisition and after delay challenge. E1 did not impact ChAT-IR neuron number in the medial septum (MS) or horizontal/vertical diagonal bands. In a comparison study, 17ß-E2 increased MS ChAT-IR neuron number. Findings indicate that E1 negatively impacts spatial working memory and memory retention, and does not increase ChAT-IR neuron number in basal forebrain, as does 17ß-E2. Thus, data from prior studies suggest that 17ß-E2 and CEE can enhance cognition and increase number of ChAT-IR basal forebrain neurons, while here we show that E1 does not induce these effects. Findings from preclinical basic science studies can inform the design of specific combinations of estrogens that could be beneficial to the brain and cognition. Accumulating data suggest that E1 is not likely to be among these key beneficial estrogens.

Remote, unsupervised functional motor task evaluation in older adults across the United States using the MindCrowd electronic cohort.

The COVID-19 pandemic has impacted the ability to evaluate motor function in older adults, as motor assessments typically require face-to-face interaction. This study tested whether motor function can be assessed at home. One hundred seventy-seven older adults nationwide (recruited through the MindCrowd electronic cohort) completed a brief functional upper-extremity assessment at home and unsupervised. Performance data were compared to data from an independent sample of community-dwelling older adults (N=250) assessed by an experimenter in-lab. The effect of age on performance was similar between the in-lab and at-home groups for both the dominant and non-dominant hand. Practice effects were also similar between the groups. Assessing upper-extremity motor function remotely is feasible and reliable in community-dwelling older adults. This test offers a practical solution in response to the COVID-19 pandemic and telehealth practice and other research involving remote or geographically isolated individuals.

Transient ACE (Angiotensin-Converting Enzyme) Inhibition Suppresses Future Fibrogenic Capacity and Heterogeneity of Cardiac Fibroblast Subpopulations.

Transient ACE (angiotensin-converting enzyme) inhibition in spontaneously hypertensive rats is known to protect against future injury-induced cardiac inflammation, fibrosis, and dysfunction; however, the mechanisms of protection have not been delineated. Here, we used single-cell RNA sequencing to test the hypothesis that transient ACE inhibitor treatment would induce a persistent shift in cardiac fibroblast subpopulations. Adult male spontaneously hypertensive rats (11 weeks old, hypertensive with cardiac hypertrophy) were treated for 2 weeks with an ACE inhibitor, enalapril (30 mg/kg per day, PO), or water (untreated spontaneously hypertensive rats) followed by a 2-week washout period (n=7/group). Cardiac fibroblasts were isolated from the left ventricle and subjected to single-cell RNA sequencing. Nine clusters of fibroblasts were identified, with 98% of cells in clusters 0 to 6. The transient treatment produced significant changes both within and across clusters. Cluster 1 depicted a highly fibrogenic gene profile, with cluster 6 serving as a gateway to cluster 1. Transient ACE inhibition depleted the gateway and expanded cluster 0, which was the least fibrogenic profile. Moreover, within cluster 1 fibroblasts, ACE inhibition reduced expression of individual fibrosis genes (eg, COL1A1, COL3A1, and FN1; all P<1×10-35). Clusters 2 to 5 reflected proliferative, moderately fibrogenic, translationally active, and less inflammatory subsets of fibroblasts, all of which exhibited attenuated fibrogenic gene expression after transient ACE inhibition. In conclusion, transient ACE inhibition shifts cardiac fibroblast subpopulations and degree of activation resulting in an overall reduced fibrogenic phenotype.

Remote, Unsupervised Functional Motor Task Evaluation in Older Adults across the United States Using the MindCrowd Electronic Cohort.

COVID-19 has impacted the ability to evaluate motor function in older adults, as motor assessments typically require face-to-face interaction. One hundred seventy-seven older adults nationwide completed an unsupervised functional upper-extremity assessment at home. Data were compared to data from an independent sample of community-dwelling older adults (N = 250) assessed in lab. The effect of age on performance was similar between the in-lab and at-home groups. Practice effects were also similar. Assessing upper-extremity motor function remotely is feasible and reliable in community-dwelling older adults. This test offers a practical solution for telehealth practice and other research involving remote or geographically isolated individuals.

Medroxyprogesterone acetate impairs memory and alters the GABAergic system in aged surgically menopausal rats.

In women, medroxyprogesterone acetate (MPA) is the most commonly used progestin component of hormone therapy (HT). In vitro, MPA negatively impacts markers of neuronal health and exacerbates experimentally-induced neurotoxicity. There is in vitro evidence that these factors are driven by GABAergic and neurotrophic systems. Whether these effects translate to a negative impact on brain function has not been tested in vivo, clinically or preclinically. Here we evaluate the mnemonic and neurobiological effects of MPA in the surgically menopausal rat. Aged ovariectomized (OVX) rats were given subcutaneous vehicle, natural progesterone, low-dose MPA or high-dose MPA. Multiple cognitive domains were analyzed via the water radial-arm maze (WRAM) and Morris maze (MM). Cognitive brain regions were assayed for changes in the GABAergic system by evaluating GAD protein, the synthesizing enzyme for GABA, and neurotrophins. On the WRAM, both progestin types impaired learning. Further, high-dose MPA impaired delayed memory retention on the WRAM, and exacerbated overnight forgetting on the MM. While neurotrophins were not affected by progesterone or MPA treatment, both progestin types altered GAD levels. MPA significantly and progesterone marginally decreased GAD levels in the hippocampus, and both MPA and progesterone significantly increased GAD levels in the entorhinal cortex. These findings suggest that MPA, the most commonly used progestin in HT, is detrimental to learning and two types of memory, and modulates the GABAergic system in cognitive brain regions, in aged surgically menopausal rats. These findings, combined with in vitro evidence that MPA is detrimental to neuronal health, indicates that MPA has negative effects for brain health and function.

A component of Premarin(®) enhances multiple cognitive functions and influences nicotinic receptor expression.

In women, ovarian hormone loss at menopause has been related to cognitive decline, and some studies suggest that estrogen-containing hormone therapy (HT) can mitigate these effects. Recently, the Women's Health Initiative study found that conjugated equine estrogens, the most commonly prescribed HT, do not benefit cognition. Isolated components of conjugated equine estrogens (tradename Premarin(®)) have been evaluated in vitro, with delta(8,9)-dehydroestrone (∆(8)E1) and equilin showing the strongest neuroprotective profiles. It has not been evaluated whether ∆(8)E1 or equilin impact cognition or the cholinergic system, which is affected by other estrogens and known to modulate cognition. Here, in middle-aged, ovariectomized rats, we evaluated the effects of ∆(8)E1 and equilin treatments on a cognitive battery and cholinergic nicotinic receptors (nAChR). Specifically, we used (125)I-labeled epibatidine binding to assay brain nicotinic receptor containing 4α and 2ß subunits (α4ß2-nAChR), since this nicotinic receptor subtype has been shown previously to be sensitive to other estrogens. ∆(8)E1 enhanced spatial working, recent and reference memory. ∆(8)E1 also decreased hippocampal and entorhinal cortex α4ß2-nAChR expression, which was related to spatial reference memory performance. Equilin treatment did not affect spatial memory or rat α4ß2-nAChR expression, and neither estrogen impacted (86)Rb(+) efflux, indicating lack of direct action on human α4ß2 nAChR function. Both estrogens influenced vaginal smear profiles, uterine weights, and serum luteinizing hormone levels, analogous to classic estrogens. The findings indicate that specific isolated Premarin(®) components differ in their ability to affect cognition and nAChR expression. Taken with the works of others showing ∆(8)E1-induced benefits on several dimensions of health-related concerns associated with menopause, this body of research identifies ∆(8)E1 as a new avenue to be investigated as a potential component of HT that may benefit brain health and function during aging.

Neuroscientists as cartographers: mapping the crossroads of gonadal hormones, memory and age using animal models.

Cognitive function is multidimensional and complex, and research in multiple species indicates it is considerably impacted by age and gonadal hormone milieu. One domain of cognitive function particularly susceptible to age-related decrements is spatial memory. Gonadal hormones can alter spatial memory, and they are potent modulators of brain microstructure and function in many of the same brain areas affected by aging. In this paper, we review decades of animal and human literature to support a tertiary model representing interactions between gonadal hormones, spatial cognition and age given that: 1) gonadal hormones change with age, 2) age impacts spatial learning and memory, and 3) gonadal hormones impact spatial learning and memory. While much has been discovered regarding these individual tenets, the compass for future aging research points toward clarifying the interactions that exist between these three points, and understanding mediating variables. Indeed, identifying and aligning the various components of the complex interactions between these tenets, including evaluations using basic science, systems, and clinical perspectives, is the optimal approach to attempt to converge the many findings that may currently appear contradictory. In fact, as discoveries are being made it is becoming clear that the findings across studies that appear contradictory are not contradictory at all. Rather, there are mediating variables that are influencing outcome and affecting the extent, and even the direction, of the effects that gonadal hormones have on cognition during aging. These mediating variables are just starting to be understood. By aligning basic scientific discoveries with clinical interpretations, we can maximize the opportunities for discoveries and subsequent interventions to allow individuals to "optimize their aging" and find their own map to cognitive health as aging ensues.

Reinventing Neuroaging Research in the Digital Age.

The worldwide average human lifespan has increased over the past century. These changing demographics demand a reinvention of experimental approaches to study the brain and aging, with the aim of better matching cognitive healthspan with human lifespan. Past studies of cognitive aging included sample sizes that tended to be underpowered, were not sufficiently representative of national population characteristics, and often lacked longitudinal assessments. As a step to address these shortcomings, we propose a framework that encourages interaction between electronic-based and face-to-face study designs. We argue that this will achieve the necessary synergy to accelerate progress in the discovery and application of personalized interventions to optimize brain and cognitive health.

ESHRD: deconvolution of brain homogenate RNA expression data to identify cell-type-specific alterations in Alzheimer's disease.

OBJECTIVE: We describe herein a bioinformatics approach that leverages gene expression data from brain homogenates to derive cell-type specific differential expression results. RESULTS: We found that differentially expressed (DE) cell-specific genes were mostly identified as neuronal, microglial, or endothelial in origin. However, a large proportion (75.7%) was not attributable to specific cells due to the heterogeneity in expression among brain cell types. Neuronal DE genes were consistently downregulated and associated with synaptic and neuronal processes as described previously in the field thereby validating this approach. We detected several DE genes related to angiogenesis (endothelial cells) and proteoglycans (oligodendrocytes). CONCLUSIONS: We present a cost- and time-effective method exploiting brain homogenate DE data to obtain insights about cell-specific expression. Using this approach we identify novel findings in AD in endothelial cells and oligodendrocytes that were previously not reported. METHODS: We derived an enrichment score for each gene using a publicly available RNA profiling database generated from seven different cell types isolated from mouse cerebral cortex. We then classified the differential expression results from 3 publicly accessible Late-Onset Alzheimer's disease (AD) studies including seven different brain regions.

Premarin improves memory, prevents scopolamine-induced amnesia and increases number of basal forebrain choline acetyltransferase positive cells in middle-aged surgically menopausal rats.

Conjugated equine estrogen (CEE) is the most commonly prescribed estrogen therapy, and is the estrogen used in the Women's Health Initiative study. While in-vitro studies suggest that CEE is neuroprotective, no study has evaluated CEE's effects on a cognitive battery and brain immunohistochemistry in an animal model. The current experiment tested whether CEE impacted: I) spatial learning, reference memory, working memory and long-term retention, as well as ability to handle mnemonic delay and interference challenges; and, II) the cholinergic system, via pharmacological challenge during memory testing and ChAT-immunoreactive cell counts in the basal forebrain. Middle-aged ovariectomized (Ovx) rats received chronic cyclic injections of either Oil (vehicle), CEE-Low (10 microg), CEE-Medium (20 microg) or CEE-High (30 microg) treatment. Relative to the Oil group, all three CEE groups showed less overnight forgetting on the spatial reference memory task, and the CEE-High group had enhanced platform localization during the probe trial. All CEE groups exhibited enhanced learning on the spatial working memory task, and CEE dose-dependently protected against scopolamine-induced amnesia with every rat receiving the highest CEE dose maintaining zero errors after scopolamine challenge. CEE also increased number of ChAT-immunoreactive neurons in the vertical diagonal band of the basal forebrain. Neither the ability to remember after a delay nor interference, nor long-term retention, was influenced by the CEE regimen used in this study. These findings are similar to those reported previously for 17 beta-estradiol, and suggest that CEE can provide cognitive benefits on spatial learning, reference and working memory, possibly through cholinergic mechanisms.

Common BACE2 Polymorphisms are Associated with Altered Risk for Alzheimer's Disease and CSF Amyloid Biomarkers in APOE ε4 Non-Carriers.

It was recently suggested that beta-site amyloid precursor protein (APP)-cleaving enzyme 2 (BACE2) functions as an amyloid beta (Aß)-degrading enzyme; in addition to its better understood role as an APP secretase. Due to this finding we sought to understand the possible genetic risk contributed by the BACE2 locus to the development of late-onset Alzheimer's disease (AD). In this study, we report that common single nucleotide polymorphism (SNP) variation in BACE2 is associated with altered AD risk in apolipoprotein E gene (APOE) epsilon 4 variant (ε4) non-carriers. In addition, in ε4 non-carriers diagnosed with AD or mild cognitive impairment (MCI), SNPs within the BACE2 locus are associated with cerebrospinal fluid (CSF) levels of Aß1-42. Further, SNP variants in BACE2 are also associated with BACE2 RNA expression levels suggesting a potential mechanism for the CSF Aß1-42 findings. Lastly, overexpression of BACE2 in vitro resulted in decreased Aß1-40 and Aß1-42 fragments in a cell line model of Aß production. These findings suggest that genetic variation at the BACE2 locus modifies AD risk for those individuals who don't carry the ε4 variant of APOE. Further, our data indicate that the biological mechanism associated with this altered risk is linked to amyloid generation or clearance possibly through BACE2 expression changes.

Family history of Alzheimer's disease alters cognition and is modified by medical and genetic factors.

In humans, a first-degree family history of dementia (FH) is a well-documented risk factor for Alzheimer's disease (AD); however, the influence of FH on cognition across the lifespan is poorly understood. To address this issue, we developed an internet-based paired-associates learning (PAL) task and tested 59,571 participants between the ages of 18-85. FH was associated with lower PAL performance in both sexes under 65 years old. Modifiers of this effect of FH on PAL performance included age, sex, education, and diabetes. The Apolipoprotein E ε4 allele was also associated with lower PAL scores in FH positive individuals. Here we show, FH is associated with reduced PAL performance four decades before the typical onset of AD; additionally, several heritable and non-heritable modifiers of this effect were identified.

Higher levels of estradiol replacement correlate with better spatial memory in surgically menopausal young and middle-aged rats.

The current study investigated whether, for spatial reference memory, age impacts (1) sensitivity to surgical ovarian hormone loss (Ovx), (2) response to estradiol therapy (ET), and (3) the relation between circulating estradiol levels and memory scores in ovary-intact sham and Ovx plus ET rats. Young, middle-aged and aged Fischer-344 rats received sham, Ovx or Ovx plus ET treatments, and were then tested on the Morris maze. After the last test trial, a probe trial was given whereby the platform was removed. Circulating estradiol levels were then determined and correlated with performance. In Study 1, Ovx facilitated learning on day one, but impaired performance after day one, in young rats. Ovx did not influence performance in middle-aged rats. In young and middle-aged Ovx rats, ET enhanced performance with higher exogenous estradiol levels correlating with better performance during testing and the probe trial. There was no relationship between endogenous estradiol levels and performance in sham young or middle-aged rats. Study 2 showed that, like middle-aged rats, aged rats were not impacted by Ovx. Further, for aged Ovx rats, the ET regimen that was beneficial at earlier ages was no longer effective during test trials, and had only minor benefits for platform localization as assessed by the probe trial. Collectively, the findings suggest that the effects of Ovx as well as responsivity to the currently utilized ET regimen changes with age. Further, there appears to be a distinction between sensitivity to Ovx and responsiveness to ET after Ovx for spatial reference memory performance.