Conjugated microporous polymers are a new class of porous materials with an extended π-conjugation in an amorphous organic framework. Owing to the wide-ranging flexibility in the choice and design of components and the available control of pore parameters, these polymers can be tailored for use in various applications, such as gas storage, electronics and catalysis. Here we report a class of cobalt/aluminium-coordinated conjugated microporous polymers that exhibit outstanding CO2 capture and conversion performance at atmospheric pressure and room temperature. These polymers can store CO2 with adsorption capacities comparable to metal-organic frameworks. The cobalt-coordinated conjugated microporous polymers can also simultaneously function as heterogeneous catalysts for the reaction of CO2 and propylene oxide at atmospheric pressure and room temperature, wherein the polymers demonstrate better efficiency than a homogeneous salen-cobalt catalyst. By combining the functions of gas storage and catalysts, this strategy provides a direction for cost-effective CO2 reduction processes.

Aggregated and oligomeric amyloid beta-protein (Abeta) is known to exhibit neurotoxicity. However, the action of Abeta monomers on neurons is not fully understood. We have studied aggregation state-dependent actions of Abeta and found an oligomer-specific effect of Abeta on lipid metabolism in neurons (Michikawa et al., 2001). Here, we show a novel function of monomeric Abeta1-40, which is the major species found in physiological fluid, as a natural antioxidant molecule that prevents neuronal death caused by transition metal-induced oxidative damage. Monomeric Abeta1-40, which is demonstrated by SDS-PAGE after treatment with glutaraldehyde, protects neurons cultured in a medium containing 1.5 microm Fe(II) without antioxidant molecules. Metal ion chelators such as EDTA, CDTA (trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid), and DTPA (diethylenetriamine-N,N,N',N",N"-penta-acetic acid, an iron-binding protein, transferrin, and antioxidant scavengers such as catalase, glutathione, and vitamin E also inhibit neuronal death under the same conditions. Monomeric Abeta1-40 inhibits neuronal death caused by Cu(II), Fe(II), and Fe(III) but does not protect neurons against H2O2-induced damage. Monomeric Abeta1-40 inhibits the reduction of Fe(III) induced by vitamin C and the generation of superoxides and prevents lipid peroxidation induced by Fe(II). Abeta1-42 remaining as a monomer also exhibits antioxidant and neuroprotective effects. In contrast, oligomeric and aggregated Abeta1-40 and Abeta1-42 lose their neuroprotective activity. These results indicate that monomeric Abeta protects neurons by quenching metal-inducible oxygen radical generation and thereby inhibiting neurotoxicity. Because aggregated Abeta is known to be an oxygen radical generator, our results provide a novel concept that the aggregation-dependent biological effects of Abeta are dualistic, being either an oxygen radical generator or its inhibitor.

Alzheimer's disease (AD) is characterized by progressive neurodegeneration and cerebral accumulation of the β-amyloid peptide (Aβ), but it is unknown what makes neurons susceptible to degeneration. We report that the TGF-β type II receptor (TβRII) is mainly expressed by neurons, and that TβRII levels are reduced in human AD brain and correlate with pathological hallmarks of the disease. Reducing neuronal TGF-β signaling in mice resulted in age-dependent neurodegeneration and promoted Aβ accumulation and dendritic loss in a mouse model of AD. In cultured cells, reduced TGF-β signaling caused neuronal degeneration and resulted in increased levels of secreted Aβ and β-secretase-cleaved soluble amyloid precursor protein. These results show that reduced neuronal TGF-β signaling increases age-dependent neurodegeneration and AD-like disease in vivo. Increasing neuronal TGF-β signaling may thus reduce neurodegeneration and be beneficial in AD. IntroductionAlzheimer's disease (AD) is a progressive neurodegenerative disease that leads to loss of cognitive function in a large number of elderly people. The human AD brain is characterized by the accumulation of β-amyloid peptide (Aβ) in extracellular plaques and hyperphosphorylated tau in intracellular neurofibrillary tangles. In addition, there is degeneration of synapses and dendrites and a progressive loss of neurons involved in memory processes (1). The cause of this degeneration in AD remains unknown, and no effective treatments are available.Survival of neurons is dependent on extracellular signals from neurotrophic factors and related factors with trophic activity (reviewed in ref.2). Levels of the neurotrophin nerve growth factor (NGF) and its receptor, tropomyosin receptor kinase A (TRKA), as well as levels of brain-derived neurotrophic factor (BDNF) and its receptor, TRKB, are lower in human AD brains than in nondemented controls (2-5). It was therefore proposed that a deficiency in neurotrophic factor signaling would promote neurodegeneration and cognitive dysfunction in AD, but this hypothesis has not been tested using specific genetic inhibition of neurotrophic factor signaling in a mouse model for AD (reviewed in refs. 2, 6).

The abnormal deposition of the amyloid ␤-protein (A␤) in the brain appears crucial to the pathogenesis of Alzheimer's disease (AD). Recent studies have suggested that highly amyloidogenic A␤ 1-42 is a cause of neuronal damage leading to AD pathogenesis and that monomeric A␤ 1-40 has less neurotoxicity than A␤ 1-42 . We found that mouse and human brain homogenates exhibit an enzyme activity converting A␤ 1-42 to A␤ 1-40 and that the major part of this converting activity is mediated by the angiotensin-converting enzyme (ACE).

We have reported previously (Michikawa, M., Fan, Q.-W., Isobe, I., and Yanagisawa, K. (2000) J. Neurochem. 74, 1008 -1016) that exogenously added recombinant human apolipoprotein E (apoE) promotes cholesterol release in an isoform-dependent manner. However, the molecular mechanism underlying this isoform-dependent promotion of cholesterol release remains undetermined. In this study, we demonstrate that the cholesterol release is mediated by endogenously synthesized and secreted apoE isoforms and clarify the mechanism underlying this apoE isoform-dependent cholesterol release using cultured astrocytes prepared from human apoE3 and apoE4 knock-in mice. Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. The amount of cholesterol released into the culture media from the apoE3-expressing astrocytes was ϳ2.5-fold greater than that from apoE4-expressing astrocytes. In contrast, the amount of apoE3 released in association with the HDL-like particles was similar to that of apoE4, and the sizes of the HDL-like particles released from apoE3-and apoE4-expressing astrocytes were similar. The molar ratios of cholesterol to apoE in the HDL fraction of the culture media of apoE3-and apoE4-expressing astrocytes were 250 ؎ 6.0 and 119 ؎ 5.1, respectively. These data indicate that apoE3 has an ability to generate similarly sized lipid particles with less number of apoE molecules than apoE4, suggesting that apoE3-expressing astrocytes can supply more cholesterol to neurons than apoE4-expressing astrocytes. These findings provide a new insight into the issue concerning the putative alteration of apoE-related cholesterol metabolism in Alzheimer's disease.Previous epidemiological studies show that an elevated serum cholesterol level is a risk factor for the development of Alzheimer's disease (AD) 1 (1-3) and that statin therapy reduces the frequency of AD (4) and dementia (5). The decreased levels of cellular cholesterol have been shown to reduce A␤ production in vitro (6) and in vivo (7). Previous studies have also shown the association of cholesterol accumulation with mature senile plaques (8) and neurofibrillary tangle-bearing neurons (9). Additionally, a recent study (10) has suggested that an increased cholesterol level in the membrane facilitates amyloid fibril formation through formation of GM1 gangliosidebound A␤, a putative endogenous seed. These findings suggest that increased cellular cholesterol levels induce high amyloid ␤-protein (A␤) production and subsequent AD development. However, several studies (11-14) have shown opposing evidence indicating that cholesterol levels in serum, cell membranes of brains, and cerebrospinal fluid are decreased in AD patients compared with those in controls. Previous studies have shown that increased dietary cholesterol levels reduce A␤ secretion (15) and that increased cellular cholesterol levels inhibit the A␤-mediated cell tox...