Alzheimer's disease (AD) is characterized by amyloid deposits of the amyloid b-peptide (Ab) in brain [1]. Ab is a 40-42 amino acid peptide that is proteolytically derived from the b-amyloid precursor protein (APP). The longer Ab42 variant aggregates more rapidly than the more abundant Ab40 [2] and is the species deposited initially in the brain in AD and Down's syndrome [3]. Several lines of evidence suggest that APP processing and Ab levels have a central role in the pathogenesis of AD. The APP gene is located on chromosome 21 (which is present in triplicate in Down's syndrome), providing an explanation for the elevated levels of APP and Ab, as well as for the AD-like pathology, observed in Down's syndrome. Moreover, mutations in genes linked to familiar early onset AD generally result in altered APP processing and an increased Ab42 ⁄ Ab40 ratio [4].It is not known how the amyloid plaques are formed. In vitro studies indicate that unstructured Ab monomers spontaneously form soluble oligomers (seeds), which, in turn, form protofibrils and mature fibrils. Other molecules could be of importance for the polymerization process in vivo, including apolipoproteins E

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Background Transdermal antipsychotic patch formulations offer potential benefits, including improved adherence. This study investigated the striatal dopamine D2 receptor occupancy with daily blonanserin transdermal patch application. Methods This open-label, Phase 2 study enrolled 18 Japanese outpatients (20 to <65 years) with schizophrenia (DSM-IV-TR criteria; total Positive and Negative Syndrome Scale [PANSS] score <120 at screening) treated with blonanserin 8 mg or 16 mg tablets. Patients continued tablets for 2-4 weeks at their current dose and were then assigned to once-daily blonanserin patches (10/20/40/60/80 mg daily) for 2-4 weeks based on the oral dose. [ 11C]raclopride PET scanning determined blonanserin striatal dopamine D2 receptor occupancy (primary endpoint). Secondary endpoints included assessment of receptor occupancy by dose, changes in PANSS and CGI-S scores, patient attitudes towards adherence, and patch adhesiveness. Results Of 18 patients who started the blonanserin tablet treatment period, 14 patients completed treatment. Mean D2 receptor occupancy for blonanserin tablets 8 mg/day (59.2%, n=5) and 16 mg/day (66.3%, n=9) was within the values for blonanserin patches: 10 mg/day (33.3%, n=3), 20 mg/day (29.9%, n=2), 40 mg/day (61.2%, n=3), 60 mg/day (59.0%, n=3), and 80 mg/day (69.9%, n=3). Occupancy generally increased with increasing blonanserin dose for both formulations with the half maximal receptor occupancy for tablets and patches associated with doses of 6.9 mg/day and 31.9 mg/day, respectively. Diurnal variability in occupancy was lower during transdermal patch treatment than during tablet treatment. Blonanserin transdermal patches were well tolerated with no major safety concerns. Conclusions Blonanserin patches (40/80 mg/day) have lower diurnal variability in occupancy than blonanserin tablets (8/16 mg/day) and patches at doses of 40 mg/day and 80 mg/day appear to be suitable alternative for blonanserin tablets at doses of 8 mg and 16 mg/day, respectively. Blonanserin patches represent a potential new treatment option for patients with schizophrenia.

Amyloid ␤-peptide (A␤) deposition into amyloid plaques is one of the invariant neuropathological features of Alzheimer's disease. Other proteins co-deposit with A␤ in plaques, and one recently identified amyloidassociated protein is the collagen-like Alzheimer amyloid plaque component CLAC. It is not known how CLAC deposition affects A␤ plaque genesis and the progress of the disease. Here, we studied the in vitro properties of CLAC purified from a mammalian expression system. CLAC displays features characteristic of a collagen protein, e.g. it forms a partly protease-resistant triple-helical structure, exhibits an intermediate affinity for heparin, and is glycosylated. Purified CLAC was also used to investigate the interaction between CLAC and A␤. Using a solid-phase binding assay, we show that CLAC bound with a similar affinity to aggregates formed by A␤-(1-40) and A␤-(1-42) and that the interaction was impaired by increasing salt concentrations. An 8-residue-long sequence located in non-collagenous domain 2 of CLAC was found to be crucial for the interaction with A␤. These findings may be useful for future therapeutic interventions aimed at finding compounds that modulate the binding of CLAC to A␤ deposits.Alzheimer's disease (AD) 1 is a progressive neurodegenerative disorder characterized by selective neuronal loss associated with intracellular neurofibrillary tangle formation and extracellular amyloid plaques (1). The major constituents of the amyloid plaques are fibrils formed from the 40 -42-residue amyloid ␤-peptide (A␤) (2). A␤ is generated from the type I transmembrane Alzheimer amyloid precursor protein by two consecutive proteolytic cleavages. The aspartyl protease ␤-secretase BACE generates the N terminus of A␤, whereas the C terminus results from the proteolytic action of the ␥-secretase complex (3). Data from genetic and biochemical studies suggest that accumulation of the longer and more amyloidogenic species of A␤, A␤42, is a primary event in the development of AD (4). For instance, autosomal dominant forms of early-onset familial AD appear to result from an increased production of A␤42 (5), and total levels of brain A␤42 correlate with cognitive decline in AD (6).Several proteins other than A␤ have been shown by immunohistochemical methods to be associated with AD amyloid plaques (7). Some of these plaque-associated proteins, e.g. apolipoprotein J (8, 9), apolipoprotein E (10), and ␣ 1 -antichymotrypsin (11), modulate peptide aggregation. In addition, constituents of the extracellular brain matrix, e.g. the heparan sulfate proteoglycans (12-14), laminin (15, 16), and collagen type IV (17), accumulate in amyloid plaques and bind to A␤. The appearance of some of these plaque-associated proteins may be indicative of a local inflammatory response to the amyloid, and others may promote A␤ aggregation or stabilize the amyloid plaques. Recently, a novel plaque-associated protein, CLAC (collagen-like Alzheimer amyloid plaque component), was identified using antibodies raised against insoluble amyloid fr...

Deposition of amyloid beta-peptide (Abeta) into amyloid plaques is one of the invariant neuropathological features of Alzheimer's disease. Proteins that codeposit with Abeta are potentially important for the pathogenesis, and a recently discovered plaque-associated protein is the collagenous Alzheimer amyloid plaque component (CLAC). In this study, we investigated the molecular interactions between Abeta aggregates and CLAC using surface plasmon resonance spectroscopy and a solid-phase binding immunoassay. We found that CLAC binds to Abeta with high affinity, that the central region of Abeta is necessary and sufficient for CLAC interaction, and that the aggregation state of Abeta as well as the presence of negatively charged residues is important. We also show that this binding results in a reduced rate of fibril elongation. Taken together, we suggest that CLAC becomes involved at an intermediate stage in the pathogenesis by binding to Abeta fibrils, including fibrils formed from peptides with truncated N- or C-termini, and thereby slows their growth.