Recent epidemiological studies suggest that diabetes mellitus is a strong risk factor for Alzheimer disease. However, the underlying mechanisms remain largely unknown. In this study, to investigate the pathophysiological interaction between these diseases, we generated animal models that reflect the pathologic conditions of both diseases. We crossed Alzheimer transgenic mice (APP23) with two types of diabetic mice (ob/ob and NSY mice), and analyzed their metabolic and brain pathology. The onset of diabetes exacerbated Alzheimer-like cognitive dysfunction without an increase in brain amyloid-β burden in double-mutant (APP + -ob/ ob) mice. Notably, APP + -ob/ob mice showed cerebrovascular inflammation and severe amyloid angiopathy. Conversely, the cross-bred mice showed an accelerated diabetic phenotype compared with ob/ob mice, suggesting that Alzheimer amyloid pathology could aggravate diabetes. Similarly, APP + -NSY fusion mice showed more severe glucose intolerance compared with diabetic NSY mice. Furthermore, high-fat diet feeding induced severe memory deficits in APP + -NSY mice without an increase in brain amyloid-β load. Here, we created Alzheimer mouse models with early onset of cognitive dysfunction. Cerebrovascular changes and alteration in brain insulin signaling might play a pivotal role in this relationship. These findings could provide insights into this intensely debated association.β-amyloid | insulin T he incidences of Alzheimer disease (AD) and diabetes mellitus (DM) are increasing at an alarming rate and have become major public health concerns (1, 2). Interestingly, numerous epidemiological studies demonstrated that diabetic patients have a significantly higher risk of developing AD, independent of the risk for vascular dementia (2, 3). These findings raise the possibility that DM may affect fundamental AD pathogenesis. A neuropathological hallmark of AD is β-amyloid peptide (Aβ) accumulation in the brain (4). Of importance, recent data showed a clear relationship between insulin and Aβ metabolism (5-7). For example, insulin increased the extracellular Aβ level by modulating γ-secretase activity (6), or by increasing its secretion from neurons (5). Insulin-degrading enzyme, a major Aβ-degrading enzyme, might be competitively inhibited by insulin, resulting in decreased Aβ degradation (7). In addition, the brain insulin-degrading enzyme level was decreased in a hyperinsulinemic Alzheimer animal model (8). Nevertheless, unexpectedly, there is no evidence that the typical pathological hallmarks of AD, including amyloid plaque, are increased in the brain of diabetic patients (9, 10). Thus, DM could affect the pathogenesis of AD through other mechanisms than modulating Aβ metabolism. One possible mechanism is cerebrovascular alteration, a common pathological change in DM and AD. Accumulating evidence suggests the importance of Aβ-induced cerebrovascular dysfunction in AD (11). Moreover, cerebrovascular disease is a major complication of DM. Vascular inflammation or oxidative stress mediated by the ...
The apical H+-coupled peptide transporter (PEPT1) and basolateral peptide transporter in human intestinal Caco-2 cells were functionally compared by the characterization of [14C]glycylsarcosine transport. The glycylsarcosine uptake via the basolateral peptide transporter was less sensitive to medium pH than uptake via PEPT1 and was not transported against the concentration gradient. Kinetic analysis indicated that glycylsarcosine uptake across the basolateral membranes was apparently mediated by a single peptide transporter. Small peptides and β-lactam antibiotics inhibited glycylsarcosine uptake by the basolateral peptide transporter, and these inhibitions were revealed to be competitive. Comparison of the inhibition constant values of various β-lactam antibiotics between PEPT1 and the basolateral peptide transporter suggested that the former had a higher affinity than the latter. A histidine residue modifier, diethyl pyrocarbonate, inhibited glycylsarcosine uptake by both transporters, although the inhibitory effect was greater on PEPT1. These findings suggest that a single facilitative peptide transporter is expressed at the basolateral membranes of Caco-2 cells and that PEPT1 and the basolateral peptide transporter cooperate in the efficient transepithelial transport of small peptides and peptidelike drugs.
Pulmonary surfactant protein D (SP-D) 3 is a member of the collectin protein family that also includes surfactant protein A (SP-A) and mannose binding lectin (1, 2). The structure of the collectins is characterized by four domains consisting of: 1) an N terminus involved in interchain disulfide bonding, 2) a collagen-like domain, 3) a coiled-coil neck domain, and 4) a carbohydrate recognition domain (CRD) (3). SP-A and mannose binding lectin contain collagenous domains consisting of 23 and 19 repeating Gly-X-Y triplets, respectively, with an interruption at the middle of the collagenous sequence (4, 5). In contrast, SP-D possesses a longer collagenous tail composed of 59 Gly-X-Y repeats without an interruption (6). These differences cause distinct oligomeric organization, with SP-A and mannose binding lectin exhibiting bouquet-like structures consisting of either six or four trimeric subunits (7) and SP-D exhibiting cruciform structures composed of four trimeric subunits (8).Lipopolysaccharide (LPS) is a principal component of the outer membrane of Gram-negative bacteria that activates macrophages and induces a variety of inflammatory mediators, including TNF-␣, IL-1, IL-6, IL-8, and interferon (9). LPS composed of O-antigen, core oligosaccharide, and lipid A is named smooth LPS, and LPS lacking O-antigen and a part of the core oligosaccharides is named rough LPS (10). Toll-like receptor 4 (TLR4) plays a critical role in recognition and signaling by LPS (11, 12). MD-2 binds directly to LPS and is required for TLR4-mediated signaling induced by LPS (13,14). Structural examination of the TLR4-MD-2 complex revealed that MD-2 binds to the concave surface of the N-terminal and central domains of TLR4 (15). A study with recombinant soluble forms of the extracellular TLR4 domain (sTLR4) and MD-2 (sMD-2) from our laboratory indicates the importance of the N-terminal region of TLR4 in MD-2 binding (16).Engineered genetic defects in the pulmonary collectins of mice have revealed their important functions in protecting the lung from microbial infections and inflammation. SP-D-null mice infected with group B Streptococcus or Haemophilus influenza by intra-tracheal instillation show increased inflammation and inflammatory cell recruitment in the lung (17). Increased pulmonary inflammation in LPS (Escherichia coli O55:B5, smooth serotype)-instilled SP-D Ϫ/Ϫ mice and wildtype mice was decreased by intratracheal administration of SP-D and pulmonary surfactant (18). Intratracheal recombinant SP-D prevents endotoxin shock in the newborn preterm
Peptide transporters PEPT1 and PEPT2 transport numerous compounds including small peptides, peptide-like drugs and nonpeptidic compounds such as valacyclovir. PEPT1 and PEPT2 show low and high affinity for most substrates, respectively, but beta-lactam antibiotics without an alpha-amino group are the only known substrates that prefer PEPT1 to PEPT2. The aim of this study was to compare the recognition and affinity of various substrates between rat PEPT1 and rat PEPT2, and to determine the structural requirements influencing the substrate affinity. [14C]Glycylsarcosine uptake by PEPT1- or PEPT2-expressing transfectant was inhibited by di- and tripeptides, but not by amino acids, tetrapeptides or most cyclic dipeptides. All dipeptides and tripeptides examined showed more potent inhibition of [14C]glycylsarcosine uptake via PEPT2 than via PEPT1, irrespective of their charge and structure. Modification of the alpha-amino group of dipeptides reduced their substrate affinity to both transporters, as compared to unmodified dipeptides, but these dipeptides still showed potent inhibitory effects on PEPT2. Among the nonpeptidic substrates tested, only the eight-amino-octanoic acid displayed stronger inhibition of [14C]glycylsarcosine uptake in PEPT1 than in PEPT2. These findings suggest that alpha- or beta-amino carbonyl function is the key structure responsible for the higher affinity for PEPT2 than for PEPT1.
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