Alzheimer's Disease Amyloid Plaques Research Articles

Tau–amyloid interactions in the rTgTauEC model of early Alzheimer's disease suggest amyloid‐induced disruption of axonal projections and exacerbated axonal pathology

Early observations of the patterns of neurofibrillary tangles and amyloid plaques in Alzheimer's disease suggested a hierarchical vulnerability of neurons for tangles, and a widespread nonspecific pattern of plaques that nonetheless seemed to correlate with the terminal zone of tangle-bearing neurons in some instances. The first neurofibrillary cortical lesions in Alzheimer's disease occur in the entorhinal cortex, thereby disrupting the origin of the perforant pathway projection to the hippocampus, and amyloid deposits are often found in the molecular layer of the dentate gyrus, which is the terminal zone of the entorhinal cortex. We modeled these anatomical changes in a transgenic mouse model that overexpresses both P301L tau (uniquely in the medial entorhinal cortex) and mutant APP/PS1 (in a widespread distribution) to examine the anatomical consequences of early tangles, plaques, or the combination. We find that tau uniformly occupies the terminal zone of the perforant pathway in tau-expressing mice. By contrast, the addition of amyloid deposits in this area leads to disruption of the perforant pathway terminal zone and apparent aberrant distribution of tau-containing axons. Moreover, human P301L tau-containing axons appear to increase the extent of dystrophic axons around plaques. Thus, the presence of amyloid deposits in the axonal terminal zone of pathological tau-containing neurons profoundly impacts their normal connectivity.

Amplified voltammetric characterization of cleavage of the biotinylated peptide by BACE1 and screening of BACE1 inhibitors

Cleavage of amyloid precursor protein (APP) by the β-site APP cleaving enzyme 1 (BACE1) is a key step in the formation of amyloid beta (Aβ) peptide, the main component of amyloid plaques in Alzheimer's disease (AD). Suppression of BACE1 activity has thus become an efficient way for the treatment of AD. In this study, BACE1 in the absence or presence of BACE1 inhibitors was exposed to the biotinylated peptide substrate-modified electrode. This step was followed by the attachment of ferrocene (Fc)-capped gold nanoparticle/streptavidin conjugates. Due to the blockage of the BACE1 activity by select inhibitors, well-defined voltammetric peaks of high signal intensity were obtained. However, featureless voltammogram was obtained upon initiating the cleavage reaction. The proposed method is simple, sensitive, and suitable for monitoring of BACE1 activity and screening of BACE1 inhibitors.

Human chorionic gonadotropin increases β-cleavage of amyloid precursor protein in SH-SY5Y cells.

Elevated levels of amyloid-β (Aβ) peptides, the main component of amyloid plaques in Alzheimer's disease, are the result of excessive β- and γ-cleavage of the amyloid precursor protein (APP) and/or impaired Aβ clearance in the brain. It has been suggested that high concentrations of luteinizing hormone (LH) in women contribute to increased Aβ generation after menopause, but the mechanism for this is incompletely understood. We investigated the effect of human chorionic gonadotropin (hCG), an LH receptor agonist, on APP β-cleavage in the SH-SY5Y neuroblastoma cell line. Treatment of these cells with hCG-induced elevated β-cleavage in a dose-dependent manner: administration of 30 mIU but not 10 mIU/ml of hCG significantly increased sAPPβ levels in the cell medium 1.7-fold as measured by ELISA. These results support the notion that LH contributes to elevated Aβ levels at least in part by increasing β-cleavage of APP by β-site APP cleaving enzyme.

Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles

The protease β-secretase 1 (Bace1) was identified through its critical role in production of amyloid-β peptides (Aβ), the major component of amyloid plaques in Alzheimer's disease. Bace1 is considered a promising target for the treatment of this pathology, but processes additional substrates, among them Neuregulin-1 (Nrg1). Our biochemical analysis indicates that Bace1 processes the Ig-containing β1 Nrg1 (IgNrg1β1) isoform. We find that a graded reduction in IgNrg1 signal strength in vivo results in increasingly severe deficits in formation and maturation of muscle spindles, a proprioceptive organ critical for muscle coordination. Further, we show that Bace1 is required for formation and maturation of the muscle spindle. Finally, pharmacological inhibition and conditional mutagenesis in adult animals demonstrate that Bace1 and Nrg1 are essential to sustain muscle spindles and to maintain motor coordination. Our results assign to Bace1 a role in the control of coordinated movement through its regulation of muscle spindle physiology, and implicate IgNrg1-dependent processing as a molecular mechanism.

Presenilins are novel substrates for TRAF6-mediated ubiquitination

Mutations in presenilins (PS1 and PS2) have been linked to the pathogenesis of early onset familial Alzheimer's disease. Presenilins function as the catalytic component of the γ-secretase protease complexes responsible for the cleavage of the amyloid precursor protein (APP), subsequent generation of amyloid-β and associated amyloid plaques in Alzheimer's disease. Biochemical and genetic studies have revealed that through interactions with several proteins, the presenilins are functionally involved in a range of cellular processes, including the regulation of intracellular calcium homeostasis. Our group has previously reported an association between presenilins and members of the tumour necrosis factor receptor-associated factor (TRAF) family of proteins. In this study we further investigated the association between TRAF6, an E3 ubiquitin ligase, and the presenilins. Here we show that the presenilin full-length holoproteins are novel substrates of TRAF6-mediated Lysine-63-linked ubiquitination. Interestingly, co-expression of catalytically active TRAF6 with the presenilins leads to decreased turnover of PS1 full-length holoprotein accompanying elevated presenilin protein levels. Similarly, while overexpression of TRAF6 increases presenilin holoprotein levels and ubiquitination in HEK293 cells, expression of catalytically deficient TRAF6 or TRAF6-deficiency leads to a reduction in presenilin protein levels and reduced PS1 ubiquitination. We also demonstrate that TRAF6 induces PS1 gene transcription in a JNK-dependent manner. Notably, we reveal that TRAF6-mediated ubiquitination of presenilin does not affect γ-secretase enzyme activity, but may regulate presenilin function in calcium signalling. Taken together, we propose that presenilins are novel substrates for TRAF6-mediated K63-linked ubiquitination and that ubiquitination of presenilins by TRAF6 increases presenilin holoprotein levels and in conditions in which TRAF6 ubiquitination of presenilins is reduced results in reduction of calcium release from the endoplasmic reticulum.

Fluorine-18 Radiolabeled Heterocycles as PET Tracers for Imaging β - Amyloid Plaques in Alzheimer’s Disease

Alzheimer's disease (AD), the most common form of dementia, is a progressive and fatal neurodegenerative disorder. The neuropathological hallmarks of AD generally revealed on postmortem brain tissue are the extracellular neuritic plaque deposits and intracellular neurofibrillary tangles. Significant evidence supports the pivotal role of β-amyloid peptides in the pathogenesis of AD. Therefore, The ability to image β-amyloid plaques in brain with noninvasive techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) may not only aid in presymptomatic identification of AD patients and differential diagnosis of patients with dementia, but also monitoring the effectiveness of anti-amyloid therapeutic strategies. For these reasons, development of β-amyloid plaque-specific imaging agents has been extensively pursued and reported. This review summarizes the current status of (18)F-labeled radioligand development for PET imaging of β-amyloid plaques. [(18)F]FDDNP is the first PET radioligand that demonstrated differential uptake and retention in the brain of AD patients, while a low signal-to-noise ratio in PET studies was indicated. At this time, [(18)F]3'-F-PIB (flutemetamol), [(18)F]AV-1 (florbetaben), [(18)F]AZD4694, and [(18)F]MK-3328 are undergoing phase II and III clinical trial. [(18)F]AV-45 (florbetapir) has recently been approved by FDA for use in patients being evaluated for Alzheimer's disease and other causes of cognitive decline. Several other (18)F-labeled radioligands based upon imidazo[1,2-a]pyridine, benzothiazole, stilbene, benzofuran, and benzoxazole core structures have also been synthesized and evaluated.

Reactive astrocytes express the potassium channel Kir4.1 in active multiple sclerosis lesions

AbstractObjectivesKir4.1, an inwardly rectifying potassium channel expressed on perivascular and perisynaptic end‐feet of astrocytes, plays a pivotal role in the spatial buffering of the potassium in the brain. A recent study showed that autoantibodies directed to Kir4.1 are detectable in the serum derived from approximately half of the patients with multiple sclerosis (MS) and clinically isolated syndrome, although their pathogenic roles should be elucidated.MethodsWe studied Kir4.1 expression in MS and control brains by immunohistochemistry.ResultsWe found that reactive astrocytes expressed an intense immunoreactivity for Kir4.1 in active demyelinating lesions of MS, active lesion edges of neuromyelitis optica, ischemic lesion edges of cerebral infarction and neurodegenerative lesions of Alzheimer's disease. Reactive astrocytes accumulated in active MS lesions coexpressed Kir4.1 and AQP4. A subset of amyloid plaques in Alzheimer's disease brains also expressed Kir4.1. In contrast, infiltrating macrophages, activated microglia and surviving oligodendrocytes in active MS lesions did not express Kir4.1. Furthermore, cultured human astrocytes expressed Kir4.1, and the expression levels were not altered by exposure to tumor necrosis factor‐α or interleukin‐1β, but were elevated by transforming growth factor‐β1.ConclusionsThese results show that reactive astrocytes abundantly express Kir4.1, and Kir4.1 immunoreactivity is not lost in active demyelinating lesions of MS.

The very many faces of presenilins and the γ-secretase complex.

Presenilin is a central, catalytic component of the γ-secretase complex which conducts intramembrane cleavage of various protein substrates. Although identified and mainly studied through its role in the development of amyloid plaques in Alzheimer disease, γ-secretase has many other important functions. The complex seems to be evolutionary conserved throughout the Metazoa, but recent findings in plants and Dictyostelium discoideum as well as in archeons suggest that its evolution and functions might be much more diversified than previously expected. In this review, a selective survey of the multitude of functions of presenilins and the γ-secretase complex is presented. Following a brief overview of γ-secretase structure, assembly and maturation, three functional aspects are analyzed: (1) the role of γ-secretase in autophagy and phagocytosis; (2) involvement of the complex in signaling related to endocytosis; and (3) control of calcium fluxes by presenilins.

Alzheimer's Aβ42 and Aβ40 peptides form interlaced amyloid fibrils

Deposition of amyloid β (Aβ) in the brain is a pathological hallmark of Alzheimer's disease. There are two major isoforms of Aβ: the 42-residue Aβ42 and the 40-residue Aβ40. The only difference between Aβ42 and Aβ40 is that Aβ42 has two extra residues at the C-terminus. The amyloid plaques in Alzheimer's brains consist of mostly Aβ42 and some plaques contain only Aβ42, even though Aβ40 concentration is several-fold more than Aβ42. Using electron paramagnetic resonance, we studied the formation of amyloid fibrils using a mixture of Aβ42 and Aβ40 in vitro. We show that Aβ42 and Aβ40 form mixed fibrils in an interlaced manner, although Aβ40 is not as efficient as Aβ42 in terms of being incorporated into Aβ42 fibrils. Our results suggest that both Aβ42 and Aβ40 would be present in amyloid plaques if in vivo aggregation of Aβ were similar to the in vitro process. Therefore, there must be some mechanisms that lead to the preferential deposition of Aβ42 at the extracellular space. Identifying such mechanisms may open new avenues for therapeutic interventions to treat Alzheimer's disease.

Backwaters and rapids on the amyloid river

The advent of amyloid imaging 1 has ushered in a new era for the field of Alzheimer disease (AD), opening the door for approaching previously unapproachable questions. No longer are researchers restricted to postmortem measurement of the neuropathologic hallmark of AD—amyloid plaques. Now, researchers are able to detect the presence and burden of amyloid in the living brain and examine how amyloid burden changes over time.

Preventing formation of reticulon 3 immunoreactive dystrophic neurites improves cognitive function in mice.

Neuritic dystrophy is one of the important pathological features associated with amyloid plaques in Alzheimer's disease (AD) and age-dependent neuronal dysfunctions. We reported previously that reticulon-3 (RTN3) immunoreactive dystrophic neurites (RIDNs) are abundantly present in the hippocampus of AD patients, in AD mouse models, and in aged wild-type mice. Transgenic mice overexpressing the human RTN3 transgene spontaneously develop RIDNs in their hippocampi, and the formation of RIDNs correlates with the appearance of RTN3 aggregation. To further elucidate whether the formation of RIDNs is reversible, we generated transgenic mice expressing wild-type human RTN3 under the control of a tetracycline-responsive promoter. Treatment with doxycycline for 2 months effectively turned off expression of the human RTN3 transgene, confirming the inducible nature of the system. However, the formation of hippocampal RIDNs was dependent on whether the transgene was turned off before or after the formation of RTN3 aggregates. When transgenic human RTN3 expression was turned off at young age, formation of RIDNs was essentially eliminated compared with the vehicle-treated transgenic mice. More importantly, a fear conditioning study demonstrated that contextual associative learning and memory in inducible transgenic mice was improved if the density of RIDNs was lowered. Additional mechanistic study suggested that a reduction in BDNF levels in transgenic mice might contribute to the reduced learning and memory in transgenic mice overexpressing RTN3. Hence, we conclude that age-dependent RIDNs cannot be effectively cleared once they have formed, and we postulate that successful prevention of RIDN formation should be initiated before RTN3 aggregation.

Synchrotron FTIR reveals lipid around and within amyloid plaques in transgenic mice and Alzheimer's disease brain

While the basis of neuronal degeneration in Alzheimer's disease (AD) continues to be debated, the amyloid cascade hypothesis remains central. Amyloid plaques are a required pathological marker for post mortem diagnosis, and Aβ peptide is regarded by most as a critical trigger at the very least. We present spectrochemical image analysis of brain tissue sections obtained with the mid-infrared beamline IRENI (InfraRed ENvironmental Imaging, Synchrotron Radiation Center, U Wisconsin-Madison), where the pixel resolution of 0.54 × 0.54 µm(2) permits analysis at sub-cellular dimensions. Spectrochemical images of dense core plaque found in hippocampus and cortex sections of two transgenic mouse models of AD (TgCRND8 and 3×Tg) are compared with plaque images from a 91 year old apoE43 human AD case. Spectral analysis was done in conjunction with histochemical stains of serial sections. A lipid membrane-like spectral signature surrounded and infiltrated the dense core plaques in all cases. Remarkable compositional similarities in early stage plaques suggest similar routes to plaque formation, regardless of genetic predisposition or mammalian origin.

β‐Amyloid induced effects on cholinergic, serotonergic, and dopaminergic neurons is differentially counteracted by anti‐inflammatory drugs

β-Amyloid (Aβ) is a small peptide that plays a potent role in synaptic plasticity as well as forms amyloid plaques in Alzheimer's disease (AD). Recent studies suggest that Aβ deposition is deleterious not only in AD, but also in Parkinson's disease (PD) and depression. This Aβ effect is associated with inflammatory processes. However, further evaluation is needed to understand how Aβ and inflammation interact and contribute to the regulation of the cholinergic, serotonergic, and dopaminergic neuronal populations. The aim of the present study was to investigate the effects of Aβ(1-42) on cholinergic neurons of the nucleus basalis of Meynert (which degenerate in AD), on serotonergic neurons of the dorsal raphe nucleus (which play a role in depression), and on dopaminergic neurons of the ventral mesencephalon (which degenerate in PD) in rat organotypic brain slices. Furthermore, we investigated whether anti-inflammatory drugs (celecoxib, citalopram, cyclooxygenase-2 inhibitor, ibuprofen, indomethacin, piclamilast) modulate or counteract Aβ-induced effects. Two-week-old organotypic brain slices of the nucleus basalis of Meynert, dorsal raphe nucleus, and ventral mesencephalon were incubated with 50 ng/ml Aβ(1-42) with or without anti-inflammatory agents for 3 days. Our results reveal that Aβ significantly decreased the number of choline acetyltransferase-positive cholinergic, tryptophan hydroxylase-positive serotonergic, and tyrosine hydroxylase-positive dopaminergic neurons and that anti-inflammatory drugs partially counteracted the Aβ-induced neuronal decline. This decline was not due to apoptotic processes (as evaluated by TUNEL, propidium iodide, caspase), oxidative stress (as measured by nitrite, catalase, or superoxide dismutase-2), or inflammation, but was most likely caused by a downregulation of these key enzymes.

Small Amphipathic Molecules Modulate Secondary Structure and Amyloid Fibril-forming Kinetics of Alzheimer Disease Peptide Aβ1–42

Amyloid fibril formation is associated with a number of debilitating systemic and neurodegenerative diseases. One of the most prominent is Alzheimer disease in which aggregation and deposition of the Aβ peptide occur. Aβ is widely considered to mediate the extensive neuronal loss observed in this disease through the formation of soluble oligomeric species, with the final fibrillar end product of the aggregation process being relatively inert. Factors that influence the aggregation of these amyloid-forming proteins are therefore very important. We have screened a library of 96 amphipathic molecules for effects on Aβ(1-42) aggregation and self-association. We find, using thioflavin T fluorescence and electron microscopy assays, that 30 of the molecules inhibit the aggregation process, whereas 36 activate fibril formation. Several activators and inhibitors were subjected to further analysis using analytical ultracentrifugation and circular dichroism. Activators typically display a 1:10 peptide:detergent stoichiometry for maximal activation, whereas the inhibitors are effective at a 1:1 stoichiometry. Analytical ultracentrifugation and circular dichroism experiments show that activators promote a mixture of unfolded and β-sheet structures and rapidly form large aggregates, whereas inhibitors induce α-helical structures that form stable dimeric/trimeric oligomers. The results suggest that Aβ(1-42) contains at least one small molecule binding site, which modulates the secondary structure and aggregation processes. Further studies of the binding of these compounds to Aβ may provide insight for developing therapeutic strategies aimed at stabilizing Aβ in a favorable conformation.

Alzheimer's Protein Lower in Brains More Stimulated

C stimulating activity, particularly in early and midlife, is associated with lower brain deposition of the major protein constituent of amyloid plaques in Alzheimer’s disease later in life, a cross-sectional study indicates. The association between cognitive activity and beta-amyloid (A-beta) protein suggests that the lifestyles of people with greater cognitive engagement may play a role in the onset and progression of Alzheimer’s disease (AD), Susan M. Landau, Ph.D., of the University of California, Berkeley, and her colleagues said online in the Archives of Neurology. PET imaging of the binding of the radiopharmaceutical carbon 11–labeled Pittsburgh Compound B ([11C]PiB) to A-beta protein showed comparable A-beta deposition in older adults in the highest cognitive activity tertile and young controls. On the other hand, older adults in the lowest cognitive activity tertile had mean cortical [11C]PiB uptake comparable with the Alzheimer’s patients (Arch. Neurol. doi:10.1001/archneurol.2011.2748). The researchers defined cognitively demanding activities in terms of activities that depended minimally on socioeconomic status, such as reading books or newspapers, writing letters or e-mails, and playing games. The greatest association was seen between higher cognitive activity from ages 6 to 40 years and lower [11C]PiB uptake, but the association between cognitive activity and lower [11C]PiB uptake existed across the life span after age, sex, and years of education were taken into account, the investigators noted. The findings “suggest a novel mechanism in which increased cognitive activity may play a direct role in reducing A-beta before disease onset,” they wrote. “Our cognitive activity measurement is likely just one of a variety of interrelated lifestyle factors that are difficult to quantify. Cognitive activity and (marginally) years of education were associated with [11C]PiB uptake (although cognitive activity and years of education were not related to one another), suggesting that these measurements may reflect a broader underlying tendency to engage in intellectual, occupational, social, and recreational activities,” Dr. Landau and her coauthors wrote. The study included 65 healthy participants with normal cognition and a mean age of 76 years and 10 with Alzheimer’s disease who had a mean age of 75 years. The 11 control participants had a mean age of 24.5 years. The healthy older adults underwent [11C]PiB PET imaging and completed an extensive neuropsychological battery between Oct. 31, 2005, and Feb. 22, 2011. They self-reported their levels of cognitively demanding activities and physical activity. Although physical activity was associated with cognitive activity in this study, it was not associated with [11C] PiB uptake. The addition of physical activity to the model also did not reduce the association between cognitive activity and PiB. This indicates that cognitive activity was the primary variable driving the association because physical activity was measured as a current function and cognitive activity was assessed as a lifelong engagement. It is plausible, they said, that people who participate in a variety of cognitively stimulating activities throughout life may develop more efficient neural processing that results in less A-beta deposition – an idea supported by findings in transgenic A-beta–expressing mice. “It is unlikely that our results reflect a single unitary cause of AD, which is a complex disease with many potential pathogenetic processes. ... However, the present findings extend previous findings that link cognitive stimulation and AD risk (an indirect downstream effect of A-beta) by providing evidence that is consistent with a model in which cognitive stimulation is linked directly to the AD-related pathology itself,” they concluded. The authors reported no relevant financial conflict of interest. CfA

Structures of Aβ17–42 Trimers in Isolation and with Five Small-Molecule Drugs Using a Hierarchical Computational Procedure

The amyloid-β protein (Aβ) oligomers are believed to be the main culprits in the cytoxicity of Alzheimer's disease (AD) and p3 peptides (Aβ17-42 fragments) are present in AD amyloid plaques. Many small-molecule or peptide-based inhibitors are known to slow down Aβ aggregation and reduce the toxicity in vitro, but their exact modes of action remain to be determined since there has been no atomic level of Aβ(p3)-drug oligomers. In this study, we have determined the structure of Aβ17-42 trimers both in aqueous solution and in the presence of five small-molecule inhibitors using a multiscale computational study. These inhibitors include 2002-H20, curcumin, EGCG, Nqtrp, and resveratrol. First, we used replica exchange molecular dynamics simulations coupled to the coarse-grained (CG) OPEP force field. These CG simulations reveal that the conformational ensemble of Aβ17-42 trimer can be described by 14 clusters with each peptide essentially adopting turn/random coil configurations, although the most populated cluster is characterized by one peptide with a β-hairpin at Phe19-Leu31. Second, these 14 dominant clusters and the less-frequent fibril-like state with parallel register of the peptides were subjected to atomistic Autodock simulations. Our analysis reveals that the drugs have multiple binding modes with different binding affinities for trimeric Aβ17-42 although they interact preferentially with the CHC region (residues 17-21). The compounds 2002-H20 and Nqtrp are found to be the worst and best binders, respectively, suggesting that the drugs may interfere at different stages of Aβ oligomerization. Finally, explicit solvent molecular dynamics of two predicted Nqtrp-Aβ17-42 conformations describe at atomic level some possible modes of action for Nqtrp.

Association of COL25A1 with Comorbid Antisocial Personality Disorder and Substance Dependence

Antisocial personality disorder (ASPD) is a psychiatric disorder characterized by a long-term pattern of manipulating, exploiting, or violating the rights of others. Subjects ascertained for genetic studies of substance dependence (SD) and diagnosed with ASPD and comorbid SD were included in a two-stage genetic association study. In the discovery stage, 627 single nucleotide polymorphisms (SNPs) located in 179 candidate genes for addiction were analyzed in a case-control cohort and family-based cohort. The significant findings were replicated in an independent case-control cohort. One SNP, rs13134663, in the collagen XXV alpha 1 gene (COL25A1) was significantly associated with ASPD in both African Americans and European Americans (smallest p values were .0002 and .0004, respectively). There was also evidence of association with the same SNP in independent samples of African American and European American cases and control subjects (p = .035 and .033, respectively). Analysis of the combined set of case-control subjects yielded an allelic p value of 9 × 10(-6) with odds ratio (95% confidence interval) of 1.3 (1.16, 1.47) (smallest p = 1 × 10(-7); Bonferroni threshold p = .00012). The COL25A1 gene, located at chromosome 4q25, encodes the collagen-like Alzheimer amyloid plaque component precursor, a type II transmembrane protein specifically expressed in neurons; it co-localizes with amyloid β in senile plaques in Alzheimer disease brains. This SNP maps to the transcription factor binding site and is conserved in 17 vertebrates, including mice and rats. Our findings suggest that COL25A1 may be associated with ASPD, especially in the context of SD.

BACE1, the Alzheimer's beta-secretase enzyme, in health and disease

The beta-amyloid (Abeta) peptide is the major constituent of amyloid plaques in Alzheimer’s disease (AD) brain and is likely to play a central role in the pathogenesis of this devastating neurodegenerative disorder. The beta-secretase, beta-site amyloid precursor protein cleaving enzyme 1 (BACE1; also called Asp2, memapsin 2), is the enzyme responsible for initiating the generation of Abeta. Thus, BACE1 is a prime drug target for the therapeutic inhibition of Abeta production for the treatment or prevention of AD. Since its discovery over 10 years ago, much has been learned about BACE1. This seminar will describe BACE1 properties, physiological functions, and dysregulation in AD. The therapeutic potential of BACE1 inhibitors for AD will also be considered. Particular focus will be placed upon our novel results demonstrating a role of BACE1 in the axon guidance of olfactory sensory neuron axons to specific odorant receptor glomeruli in the olfactory bulb and the therapeutic implications of these findings.

Amyloid-β-Heme Complex and Protein Tyrosine Nitration: Implications in Alzheimer's Desease

Amyloid-β(Aβ) is the major component of amyloid plaques in Alzheimer's disease(AD).Aβ cascade hypothesis suggested that Aβ deposition in the brain substance is a critical step which eventually leads to Alzheimer's disease.A large number of studies have shown that soluble Aβ oligomers are more toxic than Aβ aggregates and may be associated with cognitive dysfunction.The metabolism of heme was found to be changed in the brain of AD patients.Meanwhile,Aβ was found to bind to heme,forming Aβ-heme complex,which might contributed to the alteration of heme homeostasis in AD.The binding of heme to Aβ can inhibit Aβ aggregation and also can dissociate the aggregated state of Aβ,indicating that the interaction of Aβ with heme can play an important role in AD.Interestingly,Aβ-heme complex was found to possess higher peroxidase activity than heme,and we found this complex was more effective than heme in catalyzing the nitration of proteins,which imply that Aβ-heme may be the molecular link between Aβ and the widespread protein nitration in AD.Moreover,Aβ binds to heme has been shown to change the selectivity of the heme catalyzed protein nitration.These studies would help to understand the physiological roles of Aβ-heme in vivo and may be helpful for AD prevention and treatment.

New fluorinated 1,4-bis-(arylaminomethyl)- and 1,4-bis-(arylaminomethylene)benzenes as fluorescent probes for amyloid plaques in Alzheimer's disease and transmissible spongiform encephalopathies

The research into selective ligands of misfolded protein plaques in Alzheimer's disease and in transmissible spongiform encephalopathies led to compound 3, based on the Congo Red framework and bearing two trifluoromethoxy groups. Histochemical experiments on human brain tissues showed intense fluorescent staining of fibrillary deposits in both pathologies.