Alzheimer’s disease (AD) is increasingly recognized as a complex neurodegenerative disease beginning decades prior to the cognitive decline. While cognitive deficits remain the cardinal manifestation ...of AD, metabolic and non-cognitive abnormalities, such as alterations in body weight and neuroendocrine functions, are also present, often preceding the cognitive decline. Furthermore, hypothalamic dysfunction can also be a driver of AD pathology. Here we offer a brief appraisal of hypothalamic dysfunction in AD and provide insight into an underappreciated dual role of the hypothalamus as both a culprit and target of AD pathology, as well as into new opportunities for therapeutic interventions and biomarker development.
In this Review, Ishii and Iadecola examine the often-neglected metabolic and non-cognitive manifestations of Alzheimer’s disease, building a case for the hypothalamus as both a contributor and target of Alzheimer’s disease pathology and emphasizing its implications for the early diagnosis and treatment of the disease.
Dextran is a promising candidate as a nanocarrier of chemotherapeutic drugs due to its biocompatibility, biodegradability, and ability to accumulate in tumors. Furthermore, dextran derivatives ...interact with P-glycoprotein (P-gp), so we hypothesized that they may be available as tumor-specific drug delivery systems with the ability to reverse multidrug resistance. Here, to test this idea, we investigated whether dextran and its derivatives inhibit breast cancer resistance protein (BCRP), multidrug resistance associated protein 1 (MRP1), and P-gp in vitro. First, we examined their effect on the uptake of specific fluorescent substrates by inside-out Sf-9 membrane vesicles overexpressing BCRP, MRP1, and P-gp. BCRP and MRP1 were significantly inhibited by 2-hydroxypropyl-trimethylammonium-dextran of 4 and 70 kDa (Q-D4 and Q-D70) at a concentration near the clinically used concentration of dextran; however, P-gp was not inhibited. A structure–activity study showed that Q-D4, Q-D70, and 40 kDa diethylaminoethyl-dextran (DEAE-D40) significantly inhibited BCRP, while 4, 40, and 70 kDa dextrans (D4, D40, and D70), dextran sulfate (Sul-D40), and the individual saccharide components of dextran did not. These results suggest that the cationic side chains, but not the saccharides, are important for BCRP inhibition. Finally, cell-based efflux assay was conducted. Q-D4, Q-D70, and DEAE-D40 did not specifically increase the retention of Hoechst33342 in BCRP-overexpressing KB cells. Similarly, Q-D4 and Q-D70 did not affect the intracellular retention of specific fluorescent substrates in MRP1- and P-gp-overexpressing KB cells. The ineffectiveness in cellular systems is presumably due to inability of the dextran derivatives to access transporters located on the cytoplasmic side of the cell membrane.
There is accumulating evidence from epidemiological studies that changes in body weight are associated with Alzheimer’s disease (AD) from mid-life obesity increasing the risk of developing AD to ...weight loss occurring at the earliest stages of AD. Therefore, factors that regulate body weight are likely to influence the development and progression of AD. The adipocyte-derived hormone leptin has emerged as a major regulator of body weight mainly by activating hypothalamic neural circuits. Leptin also has several pleotropic effects including regulating cognitive function and having neuroprotective effects, suggesting a potential link between leptin and AD. Here, we will examine the relationship between leptin and AD by reviewing the recent evidence from cellular and animal models to human studies. We present a model where leptin has a bidirectional role in AD. Not only can alterations in leptin levels and function worsen cognitive decline and progression of AD pathology, but AD pathology, in of itself, can disrupt leptin signaling, which together would lead to a downward spiral of progressive neurodegeneration and worsening body weight and systemic metabolic deficits. Collectively, these studies serve as a framework to highlight the importance of understanding the molecular mechanisms underlying the body weight and systemic metabolic deficits in AD, which has the potential to open new avenues that may ultimately lead to novel therapeutic targets and diagnostic tools.
Alogliptin (ALG), an inhibitor of dipeptidylpeptidase-4, is used in the management of type 2 diabetes mellitus, and has a high absorption rate (>60–71%), despite its low lipophilicity (logP=−1.4). ...Here, we aimed to clarify the mechanism of its intestinal absorption. ALG uptake into Caco-2 cells was time-, temperature-, and concentration-dependent, but was not saturated at concentrations up to 10 mmol/L. The uptake was significantly inhibited by the organic anion transporting polypeptide (OATP) substrate fexofenadine and by the OATP inhibitor 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS), but was not inhibited by organic cation transporter (OCT)/organic cation/carnitine transporter (OCTN) or peptide transporter 1 (PEPT1) substrates. Grapefruit, orange, and apple juices and their constituents, which are known to strongly inhibit intestinal OATPs, significantly inhibited ALG uptake into Caco-2 cells. The pH dependence was bell-shaped, indicating the involvement of a pH-sensitive transporter. However, ALG uptake by HEK293 cells overexpressing OATP2B1, a key intestinal OATP transporter of amphiphilic drugs, was not different from that of mock cells. In a rat in vivo study, apple juice reduced systemic exposure to orally administered ALG without changing the terminal half-life. These observations suggest that intestinal absorption of ALG is carrier-mediated, and involves a fruit-juice-sensitive transporter other than OATP2B1.
Since 2019, a large number of people worldwide have been infected with severe acute respiratory syndrome coronavirus 2. Among those infected, a limited number develop severe coronavirus disease 2019 ...(COVID-19), which generally has an acute onset. The treatment of patients with severe COVID-19 is challenging. To optimize disease prognosis and effectively utilize medical resources, proactive measures must be adopted for patients at risk of developing severe COVID-19. We analyzed the data of COVID-19 patients from seven medical institutions in Tokyo and used mathematical modeling of patient blood test results to quantify and compare the predictive ability of multiple prognostic indicators for the development of severe COVID-19. A machine learning logistic regression model was used to analyze the blood test results of 300 patients. Due to the limited data set, the size of the training group was constantly adjusted to ensure that the results of machine learning were effective (e.g., recognition rate of disease severity > 80%). Lymphocyte count, hemoglobin, and ferritin levels were the best prognostic indicators of severe COVID-19. The mathematical model developed in this study enables prediction and classification of COVID-19 severity.
Weight loss is an early manifestation of Alzheimer's disease that can precede the cognitive decline, raising the possibility that amyloid-β (Aβ) disrupts hypothalamic neurons critical for the ...regulation of body weight. We previously reported that, in young transgenic mice overexpressing mutated amyloid precursor protein (Tg2576), Aβ causes dysfunction in neuropeptide Y (NPY)-expressing hypothalamic arcuate neurons before plaque formation. In this study, we examined whether Aβ causes arcuate NPY neuronal dysfunction by disrupting intracellular Ca
homeostasis. Here, we found that the L-type Ca
channel blocker nimodipine could hyperpolarize the membrane potential, decrease the spontaneous activity, and reduce the intracellular Ca
levels in arcuate NPY neurons from Tg2576 brain slices. In these neurons, there was a shift from high to low voltage-threshold activated L-type Ca
currents, resulting in increased Ca
influx closer to the resting membrane potential, an effect recapitulated by Aβ
and reversed by nimodipine. These low voltage-threshold activated L-type Ca
currents were dependent in part on calcium/calmodulin-dependent protein kinase II and IP
pathways. Furthermore, the effects on intracellular Ca
signaling by both a positive (ghrelin) and negative (leptin) modulator were blunted in these neurons. Nimodipine pretreatment restored the response to ghrelin-mediated feeding in young (3-5 months), but not older (10 months), female Tg2576 mice, suggesting that intracellular Ca
dysregulation is only reversible early in Aβ pathology. Collectively, these findings provide evidence for a key role for low-threshold activated voltage gated L-type Ca
channels in Aβ-mediated neuronal dysfunction and in the regulation of body weight.
Weight loss is one of the earliest manifestations of Alzheimer's disease (AD), but the underlying cellular mechanisms remain unknown. Disruption of intracellular Ca
homeostasis by amyloid-β is hypothesized to be critical for the early neuronal dysfunction driving AD pathogenesis. Here, we demonstrate that amyloid-β causes a shift from high to low voltage-threshold activated L-type Ca
currents in arcuate neuropeptide Y neurons. This leads to increased Ca
influx closer to the resting membrane potential, resulting in intracellular Ca
dyshomeostasis and neuronal dysfunction, an effect reversible by the L-type Ca
channel blocker nimodipine early in amyloid-β pathology. These findings highlight a novel mechanism of amyloid-β-mediated neuronal dysfunction through L-type Ca
channels and the importance of these channels in the regulation of body weight.
While cognitive decline and memory loss are the major clinical manifestations of Alzheimer's disease (AD), they are now recognized as late features of the disease. Recent failures in clinical drug ...trials highlight the importance of evaluating and treating patients with AD as early as possible and the difficulties in developing effective therapies once the disease progresses. Since the pathological hallmarks of AD including the abnormal aggregation of amyloid-beta (Aβ) and tau can occur decades before any significant cognitive decline in the preclinical stage of AD, it is important to identify the earliest clinical manifestations of AD and elucidate their underlying cellular and molecular mechanisms. Importantly, metabolic and non-cognitive manifestations of AD such as weight loss and alterations of peripheral metabolic signals can occur before the onset of cognitive symptoms and worsen with disease progression. Accumulating evidence suggests that the major culprit behind these early metabolic and non-cognitive manifestations of AD is AD pathology causing dysfunction of the hypothalamus, a brain region critical for integrating peripheral signals with essential homeostatic physiological functions. Here, we aim to highlight recent developments that address the role of AD pathology in the development of hypothalamic dysfunction associated with metabolic and non-cognitive manifestations seen in AD. Understanding the mechanisms underlying hypothalamic dysfunction in AD could give key new insights into the development of novel biomarkers and therapeutic targets.
Abstract
Increased levels of proteases, such as trypsin, in the distal intestine have been implicated in intestinal pathological conditions
1–3
. However, the players and mechanisms that underlie ...protease regulation in the intestinal lumen have remained unclear. Here we show that
Paraprevotella
strains isolated from the faecal microbiome of healthy human donors are potent trypsin-degrading commensals. Mechanistically,
Paraprevotella
recruit trypsin to the bacterial surface through type IX secretion system-dependent polysaccharide-anchoring proteins to promote trypsin autolysis.
Paraprevotella
colonization protects IgA from trypsin degradation and enhances the effectiveness of oral vaccines against
Citrobacter rodentium
. Moreover,
Paraprevotella
colonization inhibits lethal infection with murine hepatitis virus-2, a mouse coronavirus that is dependent on trypsin and trypsin-like proteases for entry into host cells
4,5
. Consistently, carriage of putative genes involved in trypsin degradation in the gut microbiome was associated with reduced severity of diarrhoea in patients with SARS-CoV-2 infection. Thus, trypsin-degrading commensal colonization may contribute to the maintenance of intestinal homeostasis and protection from pathogen infection.
Cognitive deficits are the major manifestation of Alzheimer’s disease (AD); however, weight loss can precede the mental decline and correlates with disease severity. Thus, brain circuits controlling ...body weight may be altered early in AD and could be intrinsic to AD pathobiology. In mouse models, we found that amyloid-beta, a major pathogenic factor in AD, could inhibit hypothalamic neurons in the leptin pathway, which was associated with early body weight/metabolic deficits. Ongoing research seeks to elucidate the mechanisms underlying the body weight/metabolic deficits and hypothalamic dysfunction in AD using both mouse models and clinically relevant human studies.(Presented at the 1919th Meeting, March 2, 2016)
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