CLAC (collagenous Alzheimer amyloid plaque component) is a proteolytic fragment derived from a novel membrane-bound collagen, CLAC-P/collagen type XXV, that deposits in senile plaques associated with amyloid ␤ peptides (A␤) in the brains of patients with Alzheimer's disease. We previously showed that CLAC binds to the fibrillized form of A␤ in vitro, although the mechanism and the subdomains that mediate interaction of CLAC with A␤ as well as the effect of binding of CLAC on amyloid fibril formation remain unknown. Here we show that the collagenous domain 1 of CLAC, which is rich in positively charged amino acid residues, mediates its interaction with A␤ and that this binding is mediated by an electrostatic interaction and requires formation of the triple helix structure of CLAC. The soluble form of CLAC purified from the media of cells transfected with CLAC-P inhibited fibrillization of A␤ in vitro, especially in its elongation phase. These results suggest the antiamyloidogenic roles of CLAC in the pathophysiology of Alzheimer's disease.Alzheimer's disease (AD) 1 is an elderly onset neurodegenerative disease causing dementia that is pathologically characterized by a massive accumulation of amyloid deposits in senile plaques or cerebrovasculature and of tau-rich neurofibrillary lesions (1). The principal component of the amyloid deposits is amyloid ␤ peptide (A␤), which is proteolytically produced from a transmembrane precursor, ␤APP, as 38 -43-amino acid fragments (2, 3). A␤ secreted from cells exhibits a heterogeneity in its C-terminal extent; A␤42 ending at the 42nd residue, which comprises ϳ10% of A␤40 in total secreted A␤, aggregates much faster than A␤40 (4) and deposits initially as diffuse-type plaques in AD or Down's syndrome brains (5). Moreover, missense mutations in ␤APP, presenilin 1 and presenilin 2 genes linked to early onset familial AD increase the production of A␤42 (6 -8). These findings collectively suggest that aggregation and deposition of A␤ are closely linked to the pathogenesis of AD.A number of non-A␤ proteinaceous components, e.g. apolipoprotein E (apoE), ␣1-antichymotrypsin, ␣ 2 -macroglobulin, complement component C1q, amyloid P component, have been identified associated with senile plaque amyloids (9), some of which have been shown to affect fibrillization of A␤ (10). Genetic polymorphism of apoE, especially the ⑀4 genotype, is known as the major genetic risk factor of AD (11), and accumulating evidence from experimental studies suggests that apoE may affect the fibrillization and deposition of A␤, thereby leading to AD; ablation of apoE gene reduced A␤ deposition in transgenic mice overexpressing human ␤APP, whereas further transgenic supplementation of human apoE ⑀4 gene accelerated deposition of ␤-sheet-rich A␤ (12). In vitro studies, however, showed that apoE also has an inhibitory effect on fibrillization of A␤ (13,14), implicating apoE in various aspects of ␤-amyloid formation in AD. These previous results emphasize the compelling need for the analysis of effects of other no...

PER exhibited a strong neuroprotective effect in a drug-refractory SE model, and this effect was correlated with its attenuation of seizure.

Magnetic resonance imaging (MRI) is a useful noninvasive tool used to detect lesions in clinical and veterinary medicine. The present study evaluated the suitability of a new easy-to-use compact MRI platform (M2 permanent magnet system, Aspect Imaging, Shoham, Israel) for assisting with preclinical toxicologic pathology examination of lesions in the rat brain. In order to induce brain lesions, male Sprague-Dawley rats were treated once with lithium chloride (127 mg/kg, intraperitoneal [i.p.]) followed by pilocarpine (30 mg/kg, i.p.). One week after dosing, the perfused, fixed brains were collected, analyzed by the MRI system and examined histopathologically. MRI of the brain of treated rats revealed areas of high T1 and middle to low T2 signals, when compared with the controls, in the piriform cortex, lateral thalamic nucleus, posterior paraventricular thalamic nucleus and posterior hypothalamic nucleus of the cerebrum. The altered MRI signal areas were consistent with well-circumscribed foci of neuronal cell degeneration/necrosis accompanied by glial cell proliferation. The present data demonstrated that quick analysis of fixed organs by the MRI system can detect the presence and location of toxicologic lesions and provide useful temporal information for selection of appropriate sections for histopathologic examination before routine slide preparation, especially in complex and functionally heterogeneous organs such as the brain.

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Background: Many patients with Alzheimer’s disease (AD) display circadian rhythm and sleep-wake disturbances. However, few mouse AD models exhibit these disturbances. Lemborexant, a dual orexin receptor antagonist, is under development for treating circadian rhythm disorders in dementia. Objective: Evaluation of senescence-accelerated mouse prone-8 (SAMP8) mice as a model for sleep-wake and rhythm disturbances in AD and the effect of lemborexant by assessing sleep-wake/diurnal rhythm behavior. Methods: SAMP8 and control senescence-accelerated mouse resistant-1 (SAMR1) mice received vehicle or lemborexant at light onset; plasma lemborexant and diurnal cerebrospinal fluid (CSF) orexin concentrations were assessed. Sleep-wake behavior and running wheel activity were evaluated. Results: Plasma lemborexant concentrations were similar between strains. The peak/nadir timing of CSF orexin concentrations were approximately opposite between strains. During lights-on, SAMP8 mice showed less non-rapid eye movement (non-REM) and REM sleep than SAMR1 mice. Lemborexant treatment normalized wakefulness/non-REM sleep in SAMP8 mice. During lights-off, lemborexant-treated SAMR1 mice showed increased non-REM sleep; lemborexant-treated SAMP8 mice displayed increased wakefulness. SAMP8 mice showed differences in electroencephalogram architecture versus SAMR1 mice. SAMP8 mice exhibited more running wheel activity during lights-on. Lemborexant treatment reduced activity during lights-on and increased activity in the latter half of lights-off, demonstrating a corrective effect on overall diurnal rhythm. Lemborexant delayed the acrophase of activity in both strains by approximately 1 hour. Conclusion: SAMP8 mice display several aspects of sleep-wake and rhythm disturbances in AD, notably mistimed activity. These findings provide some preclinical rationale for evaluating lemborexant in patients with AD who experience sleep-wake and rhythm disturbances.