GABAergic leptin receptor-expressing neurons in the dorsomedial hypothalamus project to brown adipose tissue-related neurons in the paraventricular nucleus of mice.

Brown adipose tissue (BAT) contributes to energy homeostasis via nonshivering thermogenesis. The BAT is densely innervated by the sympathetic nervous system (SNS) and activity of pre-autonomic neurons modulates the sympathetic outflow. Leptin, an adipocyte hormone, alters energy homeostasis and thermogenesis of BAT via several neuronal circuits; however, the cellular effects of leptin on interscapular BAT (iBAT)-related neurons in the hypothalamus remain to be determined. In this study, we used pseudorabies virus (PRV) to identify iBAT-related neurons in the paraventricular nucleus (PVN) of the hypothalamus and test the hypothesis that iBAT-related PVN neurons are modulated by leptin. Inoculation of iBAT with PRV in leptin receptor reporter mice (Lepr:EGFP) demonstrated that a population of iBAT-related PVN neurons expresses Lepr receptors. Our electrophysiological findings revealed that leptin application caused hyperpolarization in some of iBAT-related PVN neurons. Bath application of leptin also modulated excitatory and inhibitory neurotransmission to most of iBAT-related PVN neurons. Using channel rhodopsin assisted circuit mapping we found that GABAergic and glutamatergic Lepr-expressing neurons in the dorsomedial hypothalamus/dorsal hypothalamic area (dDMH/DHA) project to PVN neurons; however, connected iBAT-related PVN neurons receive exclusively inhibitory signals from Lepr-expressing dDMH/DHA neurons.

Creation of a comprehensive training and career development approach to increase the number of neurosurgeons supported by National Institutes of Health funding.

OBJECTIVE: To increase the number of independent National Institutes of Health (NIH)-funded neurosurgeons and to enhance neurosurgery research, the National Institute of Neurological Disorders and Stroke (NINDS) developed two national comprehensive programs (R25 [established 2009] for residents/fellows and K12 [2013] for early-career neurosurgical faculty) in consultation with neurosurgical leaders and academic departments to support in-training and early-career neurosurgeons. The authors assessed the effectiveness of these NINDS-initiated programs to increase the number of independent NIH-funded neurosurgeon-scientists and grow NIH neurosurgery research funding. METHODS: NIH funding data for faculty and clinical department funding were derived from the NIH, academic departments, and Blue Ridge Institute of Medical Research databases from 2006 to 2019. RESULTS: Between 2009 and 2019, the NINDS R25 funded 87 neurosurgical residents. Fifty-three (61%) have completed the award and training, and 39 (74%) are in academic practice. Compared to neurosurgeons who did not receive R25 funding, R25 awardees were twice as successful (64% vs 31%) in obtaining K-series awards and received the K-series award in a significantly shorter period of time after training (25.2 ± 10.1 months vs 53.9 ± 23.0 months; p < 0.004). Between 2013 and 2019, the NINDS K12 has supported 19 neurosurgeons. Thirteen (68%) have finished their K12 support and all (100%) have applied for federal funding. Eleven (85%) have obtained major individual NIH grant support. Since the establishment of these two programs, the number of unique neurosurgeons supported by either individual (R01 or DP-series) or collaborative (U- or P-series) NIH grants increased from 36 to 82 (a 2.3-fold increase). Overall, NIH funding to clinical neurological surgery departments between 2006 and 2019 increased from $66.9 million to $157.3 million (a 2.2-fold increase). CONCLUSIONS: Targeted research education and career development programs initiated by the NINDS led to a rapid and dramatic increase in the number of NIH-funded neurosurgeon-scientists and total NIH neurosurgery department funding.

Glutamatergic Preoptic Area Neurons That Express Leptin Receptors Drive Temperature-Dependent Body Weight Homeostasis.

UNLABELLED: The preoptic area (POA) regulates body temperature, but is not considered a site for body weight control. A subpopulation of POA neurons express leptin receptors (LepRb(POA) neurons) and modulate reproductive function. However, LepRb(POA) neurons project to sympathetic premotor neurons that control brown adipose tissue (BAT) thermogenesis, suggesting an additional role in energy homeostasis and body weight regulation. We determined the role of LepRb(POA) neurons in energy homeostasis using cre-dependent viral vectors to selectively activate these neurons and analyzed functional outcomes in mice. We show that LepRb(POA) neurons mediate homeostatic adaptations to ambient temperature changes, and their pharmacogenetic activation drives robust suppression of energy expenditure and food intake, which lowers body temperature and body weight. Surprisingly, our data show that hypothermia-inducing LepRb(POA) neurons are glutamatergic, while GABAergic POA neurons, originally thought to mediate warm-induced inhibition of sympathetic premotor neurons, have no effect on energy expenditure. Our data suggest a new view into the neurochemical and functional properties of BAT-related POA circuits and highlight their additional role in modulating food intake and body weight. SIGNIFICANCE STATEMENT: Brown adipose tissue (BAT)-induced thermogenesis is a promising therapeutic target to treat obesity and metabolic diseases. The preoptic area (POA) controls body temperature by modulating BAT activity, but its role in body weight homeostasis has not been addressed. LepRb(POA) neurons are BAT-related neurons and we show that they are sufficient to inhibit energy expenditure. We further show that LepRb(POA) neurons modulate food intake and body weight, which is mediated by temperature-dependent homeostatic responses. We further found that LepRb(POA) neurons are stimulatory glutamatergic neurons, contrary to prevalent models, providing a new view on thermoregulatory neural circuits. In summary, our study significantly expands our current understanding of central circuits and mechanisms that modulate energy homeostasis.

Increased Susceptibility of Humanized NSG Mice to Panton-Valentine Leukocidin and Staphylococcus aureus Skin Infection.

Staphylococcus aureus is a leading cause of skin and soft-tissue infections worldwide. Mice are the most commonly used animals for modeling human staphylococcal infections. However a supra-physiologic S. aureus inoculum is required to establish gross murine skin pathology. Moreover, many staphylococcal factors, including Panton-Valentine leukocidin (PVL) elaborated by community-associated methicillin-resistant S. aureus (CA-MRSA), exhibit selective human tropism and cannot be adequately studied in mice. To overcome these deficiencies, we investigated S. aureus infection in non-obese diabetic (NOD)/severe combined immune deficiency (SCID)/IL2rγnull (NSG) mice engrafted with human CD34+ umbilical cord blood cells. These "humanized" NSG mice require one to two log lower inoculum to induce consistent skin lesions compared with control mice, and exhibit larger cutaneous lesions upon infection with PVL+ versus isogenic PVL- S. aureus. Neutrophils appear important for PVL pathology as adoptive transfer of human neutrophils alone to NSG mice was sufficient to induce dermonecrosis following challenge with PVL+ S. aureus but not PVL- S. aureus. PMX53, a human C5aR inhibitor, blocked PVL-induced cellular cytotoxicity in vitro and reduced the size difference of lesions induced by the PVL+ and PVL- S. aureus, but PMX53 also reduced recruitment of neutrophils and exacerbated the infection. Overall, our findings establish humanized mice as an important translational tool for the study of S. aureus infection and provide strong evidence that PVL is a human virulence factor.

Il10 deficiency rebalances innate immunity to mitigate Alzheimer-like pathology.

The impact of inflammation suppressor pathways on Alzheimer's disease (AD) evolution remains poorly understood. Human genetic evidence suggests involvement of the cardinal anti-inflammatory cytokine, interleukin-10 (IL10). We crossed the APP/PS1 mouse model of cerebral amyloidosis with a mouse deficient in Il10 (APP/PS1(+)Il10(-/-)). Quantitative in silico 3D modeling revealed activated Aß phagocytic microglia in APP/PS1(+)Il10(-/-) mice that restricted cerebral amyloidosis. Genome-wide RNA sequencing of APP/PS1(+)Il10(-/-) brains showed selective modulation of innate immune genes that drive neuroinflammation. Il10 deficiency preserved synaptic integrity and mitigated cognitive disturbance in APP/PS1 mice. In vitro knockdown of microglial Il10-Stat3 signaling endorsed Aß phagocytosis, while exogenous IL-10 had the converse effect. Il10 deficiency also partially overcame inhibition of microglial Aß uptake by human Apolipoprotein E. Finally, the IL-10 signaling pathway was abnormally elevated in AD patient brains. Our results suggest that "rebalancing" innate immunity by blocking the IL-10 anti-inflammatory response may be therapeutically relevant for AD.

Leptin receptor neurons in the dorsomedial hypothalamus are key regulators of energy expenditure and body weight, but not food intake.

OBJECTIVE: Leptin responsive neurons play an important role in energy homeostasis, controlling specific autonomic, behavioral, and neuroendocrine functions. We have previously identified a population of leptin receptor (LepRb) expressing neurons within the dorsomedial hypothalamus/dorsal hypothalamic area (DMH/DHA) which are related to neuronal circuits that control brown adipose tissue (BAT) thermogenesis. Intra-DMH leptin injections also activate sympathetic outflow to BAT, but whether such effects are mediated directly via DMH/DHA LepRb neurons and whether this is physiologically relevant for whole body energy expenditure and body weight regulation has yet to be determined. METHODS: We used pharmacosynthetic receptors (DREADDs) to selectively activate DMH/DHA LepRb neurons. We further deleted LepRb with virally driven cre-recombinase from DMH/DHA neurons and determined the physiological importance of DMH/DHA LepRb neurons in whole body energy homeostasis. RESULTS: Neuronal activation of DMH/DHA LepRb neurons with DREADDs promoted BAT thermogenesis and locomotor activity, which robustly induced energy expenditure (p < 0.001) and decreases body weight (p < 0.001). Similarly, intra-DMH/DHA leptin injections normalized hypothermia and attenuated body weight gain in leptin-deficient ob/ob mice. Conversely, ablation of LepRb from DMH/DHA neurons remarkably drives weight gain (p < 0.001) by reducing energy expenditure (p < 0.001) and locomotor activity (p < 0.001). The observed changes in body weight were largely independent of food intake. CONCLUSION: Taken together, our data highlight that DMH/DHA LepRb neurons are sufficient and necessary to regulate energy expenditure and body weight.

Regulation of leptin receptor-expressing neurons in the brainstem by TRPV1.

The central nervous system plays a critical role in the regulation of feeding behavior and whole-body metabolism via controlling the autonomic output to the visceral organs. Activity of the parasympathetic neurons in the dorsal motor nucleus of the vagus (DMV) determines the vagal tone and thereby modulates the function of the subdiaphragmatic organs. Leptin is highly involved in the regulation of food intake and alters neuronal excitability of brainstem neurons. Transient receptor potential vanilloid type 1 (TRPV1) has also been shown to increase neurotransmission in the brainstem and we tested the hypothesis that TRPV1 regulates presynaptic neurotransmitter release to leptin receptor-expressing (LepRb(EGFP)) DMV neurons. Whole-cell patch-clamp recordings were performed to determine the effect of TRPV1 activation on excitatory and inhibitory postsynaptic currents (EPSC, IPSC) of LepRb(EGFP) neurons in the DMV. Capsaicin, a TRPV1 agonist increased the frequency of miniature EPSCs in 50% of LepRb(EGFP) neurons without altering the frequency of miniature IPSCs in the DMV. Stomach-projecting LepRb(EGFP) neurons were identified in the DMV using the transsynaptic retrograde viral tracer PRV-614. Activation of TRPV1 increased the frequency of mEPSC in ~50% of stomach-related LepRb(EGFP) DMV neurons. These data demonstrate that TRPV1 increases excitatory neurotransmission to a subpopulation of LepRb(EGFP) DMV neurons via presynaptic mechanisms and suggest a potential interaction between TRPV1 and leptin signaling in the DMV.

MyD88 is dispensable for cerebral amyloidosis and neuroinflammation in APP/PS1 transgenic mice.

Activated microglia are associated with amyloid plaques in transgenic mouse models of cerebral amyloidosis and in human Alzheimer disease; yet, their implication in Alzheimer disease pathogenesis remains unclear. It has been suggested that microglia play dual roles depending on the context of activation, contributing negatively to disease pathogenesis by secreting proinflammatory innate cytokines or performing a beneficial role via phagocytosis of amyloid beta (Aß) deposits. Toll-like receptors, most of which signal through the adaptor protein myeloid differentiation factor 88 (MyD88), have been suggested as candidate Aß innate pattern recognition receptors. It was recently reported that MyD88 deficiency reduced brain amyloid pathology and microglial activation. To assess a putative role of MyD88 in cerebral amyloidosis and glial activation in APPswe/PS1ΔE9 (APP/PS1) mice, we crossed MyD88-deficient (MyD88(-/-)) mice with APP/PS1 mice, interbred first filial offspring, and studied APP/PS1 MyD88(+/+), APP/PS1 MyD88(+/-), and APP/PS1 MyD88(-/-) cohorts. Biochemical analysis of detergent-soluble and detergent-insoluble Aß1-40 or Aß1-42 in brain homogenates did not reveal significant between-group differences. Furthermore, no significant differences were observed on amyloid plaque load or soluble fibrillar Aß by quantitative immunohistochemical analysis. In addition, neither activated microglia nor astrocytes differed among the three groups. These data suggest that MyD88 signaling is dispensable for Aß-induced glial activation and does not significantly affect the nature or extent of cerebral ß-amyloidosis in APP/PS1 mice.

Octyl gallate markedly promotes anti-amyloidogenic processing of APP through estrogen receptor-mediated ADAM10 activation.

Our previous studies showed that the green tea-derived polyphenolic compound (-)-epigallocatechin-3 gallate (EGCG) reduces amyloid-ß (Aß) production in both neuronal and mouse Alzheimer's disease (AD) models in concert with activation of estrogen receptor-α/phosphatidylinositide 3-kinase/protein kinase B (ERα/PI3K/Akt) signaling and anti-amyloidogenic amyloid precursor protein (APP) α-secretase (a disintegrin and metallopeptidase domain-10, ADAM10) processing. Since the gallate moiety in EGCG may correspond to the 7α position of estrogen, thereby facilitating ER binding, we extensively screened the effect of other gallate containing phenolic compounds on APP anti-amyloidogenic processing. Octyl gallate (OG; 10 µM), drastically decreased Aß generation, in concert with increased APP α-proteolysis, in murine neuron-like cells transfected with human wild-type APP or "Swedish" mutant APP. OG markedly increased production of the neuroprotective amino-terminal APP cleavage product, soluble APP-α (sAPPα). In accord with our previous study, these cleavage events were associated with increased ADAM10 maturation and reduced by blockade of ERα/PI3k/Akt signaling. To validate these findings in vivo, we treated Aß-overproducing Tg2576 mice with OG daily for one week by intracerebroventricular injection and found decreased Aß levels associated with increased sAPPα. These data indicate that OG increases anti-amyloidogenic APP α-secretase processing by activation of ERα/PI3k/Akt signaling and ADAM10, suggesting that this compound may be an effective treatment for AD.

A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric aß, and frank neuronal loss.

Alzheimer's disease (AD) is hallmarked by amyloid plaques, neurofibrillary tangles, and widespread cortical neuronal loss (Selkoe, 2001). The "amyloid cascade hypothesis" posits that cerebral amyloid sets neurotoxic events into motion that precipitate Alzheimer dementia (Hardy and Allsop, 1991). Yet, faithful recapitulation of all AD features in widely used transgenic (Tg) mice engineered to overproduce Aß peptides has been elusive. We have developed a Tg rat model (line TgF344-AD) expressing mutant human amyloid precursor protein (APPsw) and presenilin 1 (PS1ΔE9) genes, each independent causes of early-onset familial AD. TgF344-AD rats manifest age-dependent cerebral amyloidosis that precedes tauopathy, gliosis, apoptotic loss of neurons in the cerebral cortex and hippocampus, and cognitive disturbance. These results demonstrate progressive neurodegeneration of the Alzheimer type in these animals. The TgF344-AD rat fills a critical need for a next-generation animal model to enable basic and translational AD research.

Integration of sensory information via central thermoregulatory leptin targets.

The adipocyte derived hormone leptin acts in the brain to regulate body weight, food intake and energy expenditure. Even though it is well accepted that leptin regulates energy expenditure at least in part by modulating thermogenesis, the exact mechanisms are not clear. Particularly, it is unclear which central circuits regulate thermogenic leptin actions and if and how these may interact with feeding circuits. Within the last decade our understanding of central thermoregulatory circuits has increased substantially and allowed the identification of leptin target neurons (those expressing the long form leptin receptor - LepRb) that are involved in the sympathetic control of the heat generating brown adipose tissue (BAT). Indeed, LepRb neurons in the preoptic area and dorsomedial hypothalamus are part of the known thermoregulatory circuits controlling sympathetic premotor neurons that are located in the raphe pallidus. Thermoregulatory control and food intake are both regulated by leptin signaling pathways, even though distinct neuronal pathways have been described, respectively. Nevertheless, feeding status and control of body temperature and energy expenditure are tightly interconnected, but it is unknown how these aspects are connected within leptin signaling pathways to result in appropriate output signals (e.g. BAT thermogenesis). Indeed, cold-induced thermogenesis is potently blocked during fasting, which instead triggers an active decrease in energy expenditure and body temperature, a state known as torpor. In this article we will review recent data characterizing central thermoregulatory LepRb pathways and speculate on potential integration mechanisms that may relay anorexic and thermoregulatory leptin action to control energy homeostasis.

Tannic acid is a natural ß-secretase inhibitor that prevents cognitive impairment and mitigates Alzheimer-like pathology in transgenic mice.

Amyloid precursor protein (APP) proteolysis is essential for production of amyloid-ß (Aß) peptides that form ß-amyloid plaques in brains of Alzheimer disease (AD) patients. Recent focus has been directed toward a group of naturally occurring anti-amyloidogenic polyphenols known as flavonoids. We orally administered the flavonoid tannic acid (TA) to the transgenic PSAPP mouse model of cerebral amyloidosis (bearing mutant human APP and presenilin-1 transgenes) and evaluated cognitive function and AD-like pathology. Consumption of TA for 6 months prevented transgene-associated behavioral impairment including hyperactivity, decreased object recognition, and defective spatial reference memory, but did not alter nontransgenic mouse behavior. Accordingly, brain parenchymal and cerebral vascular ß-amyloid deposits and abundance of various Aß species including oligomers were mitigated in TA-treated PSAPP mice. These effects occurred with decreased cleavage of the ß-carboxyl-terminal APP fragment, lowered soluble APP-ß production, reduced ß-site APP cleaving enzyme 1 protein stability and activity, and attenuated neuroinflammation. As in vitro validation, we treated well characterized mutant human APP-overexpressing murine neuron-like cells with TA and found significantly reduced Aß production associated with less amyloidogenic APP proteolysis. Taken together, these results raise the possibility that dietary supplementation with TA may be prophylactic for AD by inhibiting ß-secretase activity and neuroinflammation and thereby mitigating AD pathology.

Optimized turmeric extract reduces ß-Amyloid and phosphorylated Tau protein burden in Alzheimer's transgenic mice.

In a previous in vitro study, the standardized turmeric extract, HSS-888, showed strong inhibition of Aß aggregation and secretion in vitro, indicating that HSS-888 might be therapeutically important. Therefore, in the present study, HSS-888 was evaluated in vivo using transgenic 'Alzheimer' mice (Tg2576) over-expressing Aß protein. Following a six-month prevention period where mice received extract HSS-888 (5mg/mouse/day), tetrahydrocurcumin (THC) or a control through ingestion of customized animal feed pellets (0.1% w/w treatment), HSS-888 significantly reduced brain levels of soluble (∼40%) and insoluble (∼20%) Aß as well as phosphorylated Tau protein (∼80%). In addition, primary cultures of microglia from these mice showed increased expression of the cytokines IL-4 and IL-2. In contrast, THC treatment only weakly reduced phosphorylated Tau protein and failed to significantly alter plaque burden and cytokine expression. The findings reveal that the optimized turmeric extract HSS-888 represents an important step in botanical based therapies for Alzheimer's disease by inhibiting or improving plaque burden, Tau phosphorylation, and microglial inflammation leading to neuronal toxicity.

CD45 deficiency drives amyloid-ß peptide oligomers and neuronal loss in Alzheimer's disease mice.

Converging lines of evidence indicate dysregulation of the key immunoregulatory molecule CD45 (also known as leukocyte common antigen) in Alzheimer's disease (AD). We report that transgenic mice overproducing amyloid-ß peptide (Aß) but deficient in CD45 (PSAPP/CD45(-/-) mice) faithfully recapitulate AD neuropathology. Specifically, we find increased abundance of cerebral intracellular and extracellular soluble oligomeric and insoluble Aß, decreased plasma soluble Aß, increased abundance of microglial neurotoxic cytokines tumor necrosis factor-α and interleukin-1ß, and neuronal loss in PSAPP/CD45(-/-) mice compared with CD45-sufficient PSAPP littermates (bearing mutant human amyloid precursor protein and mutant human presenilin-1 transgenes). After CD45 ablation, in vitro and in vivo studies demonstrate an anti-Aß phagocytic but proinflammatory microglial phenotype. This form of microglial activation occurs with elevated Aß oligomers and neural injury and loss as determined by decreased ratio of anti-apoptotic Bcl-xL to proapoptotic Bax, increased activated caspase-3, mitochondrial dysfunction, and loss of cortical neurons in PSAPP/CD45(-/-) mice. These data show that deficiency in CD45 activity leads to brain accumulation of neurotoxic Aß oligomers and validate CD45-mediated microglial clearance of oligomeric Aß as a novel AD therapeutic target.

EGCG functions through estrogen receptor-mediated activation of ADAM10 in the promotion of non-amyloidogenic processing of APP.

Estrogen depletion following menopause has been correlated with an increased risk of developing Alzheimer's disease (AD). We previously explored the beneficial effect of (-)-epigallocatechin-3-gallate (EGCG) on AD mice and found increased non-amyloidogenic processing of amyloid precursor protein (APP) through the α-secretase a disintegrin and metallopeptidase domain 10 (ADAM10). Our results in this study suggest that EGCG-mediated enhancement of non-amyloidogenic processing of APP is mediated by the maturation of ADAM10 via an estrogen receptor-α (ERα)/phosphoinositide 3-kinase/Ak-transforming dependent mechanism, independent of furin-mediated ADAM10 activation. These data support prior assertions that central selective ER modulation could be a therapeutic target for AD and support the use of EGCG as a well-tolerated alternative to estrogen therapy in the prophylaxis and treatment of this disease.

Macrophages in Alzheimer's disease: the blood-borne identity.

Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disorder clinically characterized by cognitive decline involving loss of memory, reasoning and linguistic ability. The amyloid cascade hypothesis holds that mismetabolism and aggregation of neurotoxic amyloid-beta (Abeta) peptides, which are deposited as amyloid plaques, are the central etiological events in AD. Recent evidence from AD mouse models suggests that blood-borne mononuclear phagocytes are capable of infiltrating the brain and restricting beta-amyloid plaques, thereby limiting disease progression. These observations raise at least three key questions: (1) what is the cell of origin for macrophages in the AD brain, (2) do blood-borne macrophages impact the pathophysiology of AD and (3) could these enigmatic cells be therapeutically targeted to curb cerebral amyloidosis and thereby slow disease progression? This review begins with a historical perspective of peripheral mononuclear phagocytes in AD, and moves on to critically consider the controversy surrounding their identity as distinct from brain-resident microglia and their potential impact on AD pathology.

Impact of the CD40-CD40L dyad in Alzheimer's disease.

As the number of elderly individuals rises, Alzheimer's disease (AD), marked by amyloid-beta deposition, neurofibrillary tangle formation, and low-level neuroinflammation, is expected to lead to an ever-worsening socioeconomic burden. AD pathoetiologic mechanisms are believed to involve chronic microglial activation. This phenomenon is associated with increased expression of membrane-bound CD40 with its cognate ligand, CD40 ligand (CD40L), as well as increased circulating levels of soluble forms of CD40 (sCD40) and CD40L (sCD40L). Here, we review the role of this inflammatory dyad in the pathogenesis of AD. In addition, we examine potential therapeutic strategies such as statins, flavonoids, and human umbilical cord blood transplantation, all of which have been shown to modulate CD40-CD40L interaction in mouse models of AD. Importantly, therapeutic approaches focusing on CD40-CD40L dyad regulation, either alone or in combination with amyloid-beta immunotherapy, may provide for a safe and effective AD prophylaxis or treatment in the near future.

Can peripheral leukocytes be used as Alzheimer's disease biomarkers?

Alzheimer's disease (AD) is the leading cause of dementia in elderly populations throughout the world and its incidence is on the rise. Current clinical diagnosis of AD requires intensive examination that includes neuropsychological testing and costly brain imaging techniques, and a definitive diagnosis can only be made upon postmortem neuropathological examination. Additionally, antemortem clinical AD diagnosis is typically administered following onset of cognitive and behavioral symptoms. As these symptoms emerge relatively late in disease progression, therapeutic intervention occurs after significant neurodegeneration, thereby limiting efficacy. The identification of noninvasive diagnostic biomarkers of AD is becoming increasingly important to make diagnosis more widely available to clinics with limited access to neuropsychological testing or state-of-the-art brain imaging, reduce the cost of clinical diagnosis, provide a biological measure to track the course of therapeutic intervention, and most importantly, allow for earlier diagnosis--possibly even during the prodromal phase--with hopes of therapeutic intervention prior to appreciable neurodegeneration. Circulating leukocytes are attractive candidate AD biomarkers as they can be obtained in a minimally invasive manner and are easily analyzed by widely available flow cytometry techniques. In this review, we critically analyze the potential utility of peripheral leukocytes as biological markers for AD.

Optimized turmeric extracts have potent anti-amyloidogenic effects.

Inhibition of beta-amyloid (A beta) accumulation and A beta fibril (fA beta) formation from A beta are attractive therapeutic targets for the treatment of Alzheimer's disease (AD). While previous studies have shown anti-amyloidogenic effects of curcumin in vitro and in vivo, no studies have examined optimized turmeric extracts enriched in curcuminoids or turmerones. Three standardized turmeric extracts, HSS-838, HSS-848, and HSS-888, were prepared with different chemical profiles to investigate their potential therapeutic benefits for AD. These extracts were fingerprinted by DART TOF-MS to reveal the significant chemical complexity. In addition four curcuminoids (curcumin, tetrahydrocurcumin, demethoxycurcumin and bisdemethoxycurcumin) were also examined. We measured the effects of the extracts and curcuminoids, on the aggregation of A beta by using a thioflavin T cell-free assay and the secretion of A beta from human neuronal cells (SweAPP N2A cells) in vitro. All three extracts and the curcuminoids showed dose-dependent inhibition of fA beta aggregation from A beta(1-42) in the cell-free assay, with IC(50) values of