Endocrine Dyscrasia in the Etiology and Therapy of Alzheimer's Disease.

The increase in the incidence of dementia over the last century correlates strongly with the increases in post-reproductive lifespan during this time. As post-reproductive lifespan continues to increase it is likely that the incidence of dementia will also increase unless therapies are developed to prevent, slow or cure dementia. A growing body of evidence implicates age-related endocrine dyscrasia and the length of time that the brain is subjected to this endocrine dyscrasia, as a key causal event leading to the cognitive decline associated with aging and Alzheimer's disease (AD), the major form of dementia in our society. In particular, the elevations in circulating gonadotropins, resulting from the loss of gonadal sex hormone production with menopause and andropause, appear central to the development of AD neuropathology and cognitive decline. This is supported by numerous cell biology, preclinical animal, and epidemiological studies, as well as human clinical studies where suppression of circulating luteinizing hormone and/or follicle-stimulating hormone with either gonadotropin-releasing hormone analogues, or via physiological hormone replacement therapy, has been demonstrated to halt or significantly slow cognitive decline in those with AD. This review provides an overview of past and present studies demonstrating the importance of hypothalamic-pituitary-gonadal hormone balance for normal cognitive functioning, and how targeting age-related endocrine dyscrasia with hormone rebalancing strategies provides an alternative treatment route for those with AD.

Sensory Dysfunction, Microbial Infections, and Host Responses in Alzheimer's Disease.

Sensory functions of organs of the head and neck allow humans to interact with the environment and establish social bonds. With aging, smell, taste, vision, and hearing decline. Evidence suggests that accelerated impairment in sensory abilities can reflect a shift from healthy to pathological aging, including the development of Alzheimer's disease (AD) and other neurological disorders. While the drivers of early sensory alteration in AD are not elucidated, insults such as trauma and infections can affect sensory function. Herein, we review the involvement of the major head and neck sensory systems in AD, with emphasis on microbes exploiting sensory pathways to enter the brain (the "gateway" hypothesis) and the potential feedback loop by which sensory function may be impacted by central nervous system infection. We emphasize detection of sensory changes as first-line surveillance in senior adults to identify and remove potential insults, like microbial infections, that could precipitate brain pathology.

Fueling Alzheimer's Disease: Where Does Immunometabolism Stand?

More than a century after the first description of Alzheimer's disease (AD), the road to a cure for this complex and heterogeneous neurodegenerative disorder has been paved by countless descriptive hypotheses and successive clinical trial failures. Auspiciously, the era of genome-wide association studies revolutionized the classical "neurocentric" view of AD by providing clues that brain-resident immune cells (i.e., microglia and astrocytes) are also key players in the pathological and clinical trajectory of this neurodegenerative disorder. Considering that the intercommunication among neurons, astrocytes, and microglia is fundamental for the functional organization of the brain, it is evident that the disruption of the proper functioning of this "triad" could contribute to the neuroinflammatory and neurodegenerative events that occur in the AD brain. Importantly, recent scientific progress in the burgeoning field of immunometabolism, a crossroad between metabolism and immune response, shed light on the importance of metabolic reprogramming of brain-resident immune cells in AD pathology. In this sense, the present review is aimed to summarize and discuss the current knowledge on the metabolic patterns of brain-resident immune cells during the AD continuum, putting a special focus on glucose, amino acids, and lipid metabolism. Changing the "old" picture of AD pathological basis by integrating the role of brain-resident immune cells it is imperative to establish new and feasible therapeutic interventions able to curb neuroinflammatory and neurodegenerative processes, and consequently cognitive deterioration.

Microglial modulation as a therapeutic strategy in Alzheimer's disease: Focus on microglial preconditioning approaches.

Alzheimer's disease (AD) is a progressive disease that causes an impairment of learning and memory. Despite the highly complex pathogenesis of AD, amyloid beta (Aß) deposition and neurofibrillary tangles (NFTs) formation are the main hallmarks of AD. Neuroinflammation also has a crucial role in the development of AD. As the central nervous system's innate immune cells, microglial cells are activated in AD and induce inflammation by producing pro-inflammatory mediators. However, microglial activation is not always deleterious. M2-activated microglial cells are considered anti-inflammatory cells, which develop neuroprotection. Various approaches are proposed for managing AD, yet no effective therapy is available for this disorder. Considering the potential protective role of M2 microglia in neurodegenerative disorders and the improvement of these disorders by preconditioning approaches, it can be suggested that preconditioning of microglial cells may be beneficial for managing AD progression. Therefore, this study review microglial preconditioning approaches for preventing and improving AD.

The relationship between hippocampal changes in healthy aging and Alzheimer's disease: a systematic literature review.

Introduction: Neurobiological changes in the hippocampus are a common consequence of aging. However, there are differences in the rate of decline and overall volume loss in people with no cognitive impairment compared to those with mild cognitive impairment (MCI) and Alzheimer's disease (AD). This systematic literature review was conducted to determine the relationship between hippocampal atrophy and changes in hippocampal volume in the non-cognitively impaired brain and those with MCI or AD. Methods: This systematic review was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. The PubMed database was searched up to September 15, 2022, for longitudinal magnetic resonance imaging studies reporting hippocampal atrophy or volume change in cognitively normal aging individuals and patients with MCI and/or AD. Study selection was divided into two steps: (1) identification and retrieval of relevant studies; (2) screening the studies by (a) title/abstract and (b) full text. Two teams, each consisting of two independent reviewers, determined whether the publications met the inclusion criteria for the systematic review. An evidence table was populated with data extracted from eligible publications and inclusion in the final systematic review was confirmed. Results: The systematic search identified 357 publications that were initially screened by title/abstract, of which, 115 publications were retrieved and reviewed by full text for eligibility. Seventeen publications met the eligibility criteria; however, during data extraction, two studies were determined to not meet the inclusion criteria and were excluded. The remaining 15 studies were included in the systematic review. Overall, the results of these studies demonstrated that the hippocampus and hippocampal subfields change over time, with both decreased hippocampal volume and increased rate of hippocampal atrophy observed. Hippocampal changes in AD were observed to be greater than hippocampal changes in MCI, and changes in MCI were observed to be greater than those in normal aging populations. Conclusion: Published literature suggests that the rate of hippocampal decline and extent of loss is on a continuum that begins in people without cognitive impairment and continues to MCI and AD, and that differences between no cognitive impairment, MCI, and AD are quantitative rather than qualitative.

Evaluation of pregnancy associated glycoproteins assays for on farm determination of pregnancy status in beef cattle.

Transrectal ultrasonography is known as the gold standard for pregnancy detection, but requires costly equipment and technical skills; therefore, access to an inexpensive and more user-friendly method with similar accuracy could benefit cattle producers. Detection of pregnancy-associated glycoproteins can accurately determine pregnancy in ruminants; however, usually requires specialized equipment for the assay. Thus, the objectives of these studies were to 1) validate the IDEXX Alertys OnFarm Pregnancy Test (lateral flow) and compare the accuracy of all three commercial PAG assays to transrectal ultrasonography and 2) to determine the postpartum interval necessary for clearance of pregnancy-associated glycoproteins from the previous pregnancy to avoid false positives. In study 1, blood samples from previously identified pregnant Bos taurus females from six different herds (nulliparous n = 1,205 and multiparous n = 1,539; samples collected between d 27 to 285 of gestation over a three-year period) were utilized. In study 2, postpartum females (primiparous n = 48 and multiparous n = 66) from one herd were utilized: (n = 1,066; samples collected weekly for up to 12 weeks postpartum). In study 1, level of agreement between different methods of pregnancy detection was determined by Pearson's correlation and Kappa scores. In study 2, data were analyzed as a repeated measure using the MIXED procedure of SAS with main effects of parity, days postpartum (dpp), and parity by days postpartum, then data were analyzed further using the REG procedure of SAS. In study 1, transrectal ultrasonography and lateral flow were positively correlated (r = 0.77; P <0.01), with 92.4% agreement. In study 2, the abundance of absorbance of PAGs rapidly decreased from 0 to 50 days postpartum, then continued to gradually decrease (P <0.01; r = 0.90). Prior to 42 days postpartum, PAG concentrations were sufficiently elevated resulting in false positive readings in all assays. In conclusion, there is very good agreement between transrectal ultrasonography and PAG assays, but likelihood of false positive results are highif assays are performed fewer than 42 days postpartum.

Ecological dynamics of moa extinctions reveal convergent refugia that today harbour flightless birds.

Human settlement of islands across the Pacific Ocean was followed by waves of faunal extinctions that occurred so rapidly that their dynamics are difficult to reconstruct in space and time. These extinctions included large, wingless birds called moa that were endemic to New Zealand. Here we reconstructed the range and extinction dynamics of six genetically distinct species of moa across New Zealand at a fine spatiotemporal resolution, using hundreds of thousands of process-explicit simulations of climate-human-moa interactions, which were validated against inferences of occurrence and range contraction from an extensive fossil record. These process-based simulations revealed important interspecific differences in the ecological and demographic attributes of moa and established how these differences influenced likely trajectories of geographic and demographic declines of moa following Polynesian colonization of New Zealand. We show that despite these interspecific differences in extinction dynamics, the spatial patterns of geographic range collapse of moa species were probably similar. It is most likely that the final populations of all moa species persisted in suboptimal habitats in cold, mountainous areas that were generally last and least impacted by people. We find that these refugia for the last populations of moa continue to serve as isolated sanctuaries for New Zealand's remaining flightless birds, providing fresh insights for conserving endemic species in the face of current and future threats.

Donanemab, another anti-Alzheimer's drug with risk and uncertain benefit.

Based on "reducing amyloid plaques in the brain", the U.S. Food and Drug Administration has granted accelerated and full approval for two monoclonal anti-Alzheimer's antibodies, aducanumab and lecanemab, respectively. Approval of a third antibody, donanemab, is pending. Moreover, lecanemab and donanemab are claimed to cause delay in the cognitive decline that characterizes the disease. We believe that these findings are subject to misinterpretation and statistical bias. Donanemab is claimed to cause removal of up to 86 % of cerebral amyloid and 36 % delay in cognitive decline compared to placebo. In reality, these are very small changes on an absolute scale and arguably less than what can be achieved with cholinesterase inhibitor/memantine therapy. Moreover, the "removal" of amyloid, based on the reduced accumulation of amyloid-PET tracer, most likely also reflects therapy-related tissue damage. This would also correlate with the minimal clinical effect, the increased frequency of amyloid-related imaging abnormalities, and the accelerated loss of brain volume in treated compared to placebo patients observed with these antibodies. We recommend halting approvals of anti-AD antibodies until these issues are fully understood to ensure that antibody treatment does not cause more harm than benefit to patients.

The importance of developmental programming in the beef industry.

The beef industry relies on multiple focused segments (e.g., cow-calf, stocker/feeder, and meat packing) to supply the world with beef. Thus, the potential impact of developmental programming on the beef industry needs to be evaluated with regards to the different production traits that drive profitability within each segment. For example, when nutrient restriction of dams occurred early in gestation embryo survival was decreased and the ovarian reserve of heifer progeny was negatively affected. Restriction during mid- to late gestation negatively impacted first service conception rates and pregnancy success of daughters. Even non-nutrient stress has been reported to impact transgenerational embryo development through the male progeny. Primary and secondary muscle fibers form during months two to eight (Days 60-240) of gestation. Therefore, external stimuli (nutrition or environmental) during this window have the potential to decrease the postnatal number of muscle fibers; which has an irreversible impact on animal growth and performance. Nutrient restriction during the last third of gestation resulted in decreased weaning weights, and in some instances decreased dry mater intake, hot carcass weight, and marbling scores. Protein supplementation during late gestation; however, increased weaning weight and ADG to weaning, but progeny of dams restricted in protein in late gestation had greater ribeye area. The importance of developmental programming is recognized; however, its precise application depends on comprehension of its integrated effects across the multiple-focused segments of the beef industry.

Alzheimer's Amyloid Hypothesis and Antibody Therapy: Melting Glaciers?

The amyloid cascade hypothesis for Alzheimer's disease is still alive, although heavily challenged. Effective anti-amyloid immunotherapy would confirm the hypothesis' claim that the protein amyloid-beta is the cause of the disease. Two antibodies, aducanumab and lecanemab, have been approved by the U.S. Food and Drug Administration, while a third, donanemab, is under review. The main argument for the FDA approvals is a presumed therapy-induced removal of cerebral amyloid deposits. Lecanemab and donanemab are also thought to cause some statistical delay in the determination of cognitive decline. However, clinical efficacy that is less than with conventional treatment, selection of amyloid-positive trial patients with non-specific amyloid-PET imaging, and uncertain therapy-induced removal of cerebral amyloids in clinical trials cast doubt on this anti-Alzheimer's antibody therapy and hence on the amyloid hypothesis, calling for a more thorough investigation of the negative impact of this type of therapy on the brain.

Meta-Analysis in Transgenic Alzheimer's Disease Mouse Models Reveals Opposite Brain Network Effects of Amyloid-ß and Phosphorylated Tau Proteins.

Background: Cognitive deficits observed in Alzheimer's disease (AD) patients have been correlated with altered hippocampal activity. Although the mechanism remains under extensive study, neurofibrillary tangles and amyloid plaques have been proposed as responsible for brain activity alterations. Aiming to unveil the mechanism, researchers have developed several transgenic models of AD. Nevertheless, the variability in hippocampal oscillatory alterations found in different genetic backgrounds and ages remains unclear. Objective: To assess the oscillatory alterations in relation to animal developmental age and protein inclusion, amyloid-ß (Aß) load, and abnormally phosphorylated tau (pTau), we reviewed and analyzed the published data on peak power, frequency, and quantification of theta-gamma cross-frequency coupling (modulation index values). Methods: To ensure that the search was as current as possible, a systematic review was conducted to locate and abstract all studies published from January 2000 to February 2023 that involved in vivo hippocampal local field potential recording in transgenic mouse models of AD. Results: The presence of Aß was associated with electrophysiological alterations that are mainly reflected in power increases, frequency decreases, and lower modulation index values. Concomitantly, pTau accumulation was associated with electrophysiological alterations that are mainly reflected in power decreases, frequency decreases, and no significant alterations in modulation index values. Conclusions: In this study, we showed that electrophysiological parameters are altered from prodromal stages to the late stages of pathology. Thus, we found that Aß deposition is associated with brain network hyperexcitability, whereas pTau deposition mainly leads to brain network hypoexcitability in transgenic models.

Reconstructing colonization dynamics to establish how human activities transformed island biodiversity.

Drivers and dynamics of initial human migrations across individual islands and archipelagos are poorly understood, hampering assessments of subsequent modification of island biodiversity. We developed and tested a new statistical-simulation approach for reconstructing the pattern and pace of human migration across islands at high spatiotemporal resolutions. Using Polynesian colonisation of New Zealand as an example, we show that process-explicit models, informed by archaeological records and spatiotemporal reconstructions of past climates and environments, can provide new and important insights into the patterns and mechanisms of arrival and establishment of people on islands. We find that colonisation of New Zealand required there to have been a single founding population of approximately 500 people, arriving between 1233 and 1257 AD, settling multiple areas, and expanding rapidly over both North and South Islands. These verified spatiotemporal reconstructions of colonisation dynamics provide new opportunities to explore more extensively the potential ecological impacts of human colonisation on New Zealand's native biota and ecosystems.

Fabrication and Characterization of Quad-Component Bioinspired Hydrogels to Model Elevated Fibrin Levels in Central Nervous Tissue Scaffolds.

Multicomponent interpenetrating polymer network (mIPN) hydrogels are promising tissue-engineering scaffolds that could closely resemble key characteristics of native tissues. The mechanical and biochemical properties of mIPNs can be finely controlled to mimic key features of target cellular microenvironments, regulating cell-matrix interactions. In this work, we fabricated hydrogels made of collagen type I (Col I), fibrin, hyaluronic acid (HA), and poly (ethylene glycol) diacrylate (PEGDA) using a network-by-network fabrication approach. With these mIPNs, we aimed to develop a biomaterial platform that supports the in vitro culture of human astrocytes and potentially serves to assess the effects of the abnormal deposition of fibrin in cortex tissue and simulate key aspects in the progression of neuroinflammation typically found in human pathologies such as Alzheimer's disease (AD), Parkinson's disease (PD), and tissue trauma. Our resulting hydrogels closely resembled the complex modulus of AD human brain cortex tissue (~7.35 kPa), promoting cell spreading while allowing for the modulation of fibrin and hyaluronic acid levels. The individual networks and their microarchitecture were evaluated using confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). Human astrocytes were encapsulated in mIPNs, and negligible cytotoxicity was observed 24 h after the cell encapsulation.

Plasma γ-Aminobutyric Acid (GABA) Concentrations in Lactating Holstein Cows during Thermoneutral and Heat Stress Conditions and Their Relationships with Circulating Glucose, Insulin and Progesterone Levels.

Heat-stressed lactating dairy cattle exhibit unique metabolic symptoms, many of which are undoubtedly involved in heat-induced subfertility. Because of its known systemic effects, we hypothesized that γ-aminobutyric acid (GABA) participates in the regulation of insulin and progesterone during heat stress. Multiparous lactating Holstein cows (n = 6) were studied during four experimental periods: (1) thermoneutral (TN; d 1-5), (2) TN + hyperinsulinemic-hypoglycemic clamp (d 6-10), (3) heat stress (HS; d 16-20), and (4) HS + euglycemic clamp (d 21-25). Blood samples were collected once daily via coccygeal venipuncture into heparinized evacuated tubes. Analysis of GABA concentrations from all four treatment periods yielded no differences. In direct comparison to TN concentrations, plasma GABA tended to decrease during the HS period (16.57 ± 2.64 vs. 13.87 ± 2.28 ng/mL, respectively, p = 0.06). Both milk production and plasma insulin were moderately correlated with plasma GABA (r = 0.35, p < 0.01; r = -0.32, p < 0.01). Plasma progesterone was correlated with plasma GABA concentrations during TN but not HS periods. These results are the first to indicate that peripheral GABA could be involved in the regulation of factors known to affect production and reproduction during heat stress. More research is needed to determine its precise role(s).

Developmental programming of the ovarian reserve in livestock.

Mammalian females are born with a finite number of follicles in their ovaries that is referred to as the ovarian reserve. There is a large amount of variation between females in the number of antral follicles that they are born with, but this number is positively correlated to size of the ovarian reserve, has a strong repeatability within a female, and a moderate heritability. Although the heritability is moderate, numerous external factors including health, nutrition, ambient temperature, and litter size influence the size and function of the ovarian reserve throughout life. Depletion of the ovarian reserve contributes to reproductive senescence, and genetic and epigenetic factors can lead to a more rapid decline in follicle numbers in some females than others. The relationship of the size of the ovarian reserve to development of the reproductive tract and fertility is generally positive, although some studies report antagonistic associations of these traits. It seems likely that management decisions and environmental factors that result in epigenetic modifications to the genome throughout life may cause variability in the function of ovarian genes that influence fecundity and fertility, leading to differences in reproductive longevity among females born with ovarian reserves of similar size. This review summarizes our current understanding of factors influencing size of the ovarian reserve in cattle, sheep, and pigs and the relationship of the ovarian reserve to reproductive tract development and fertility. It provides strategies to apply this knowledge to improve diagnostics for better assessment of fertility and reproductive longevity in female livestock.

Label-Free In Situ Chemical Characterization of Amyloid Plaques in Human Brain Tissues.

The accumulation of amyloid plaques and increased brain redox burdens are neuropathological hallmarks of Alzheimer's disease. Altered metabolism of essential biometals is another feature of Alzheimer's, with amyloid plaques representing sites of disturbed metal homeostasis. Despite these observations, metal-targeting disease treatments have not been therapeutically effective to date. A better understanding of amyloid plaque composition and the role of the metals associated with them is critical. To establish this knowledge, the ability to resolve chemical variations at nanometer length scales relevant to biology is essential. Here, we present a methodology for the label-free, nanoscale chemical characterization of amyloid plaques within human Alzheimer's disease tissue using synchrotron X-ray spectromicroscopy. Our approach exploits a C-H carbon absorption feature, consistent with the presence of lipids, to visualize amyloid plaques selectively against the tissue background, allowing chemical analysis to be performed without the addition of amyloid dyes that alter the native sample chemistry. Using this approach, we show that amyloid plaques contain elevated levels of calcium, carbonates, and iron compared to the surrounding brain tissue. Chemical analysis of iron within plaques revealed the presence of chemically reduced, low-oxidation-state phases, including ferromagnetic metallic iron. The zero-oxidation state of ferromagnetic iron determines its high chemical reactivity and so may contribute to the redox burden in the Alzheimer's brain and thus drive neurodegeneration. Ferromagnetic metallic iron has no established physiological function in the brain and may represent a target for therapies designed to lower redox burdens in Alzheimer's disease. Additionally, ferromagnetic metallic iron has magnetic properties that are distinct from the iron oxide forms predominant in tissue, which might be exploitable for the in vivo detection of amyloid pathologies using magnetically sensitive imaging. We anticipate that this label-free X-ray imaging approach will provide further insights into the chemical composition of amyloid plaques, facilitating better understanding of how plaques influence the course of Alzheimer's disease.