Generation and deposition of the amyloid b (Ab) peptide following proteolytic processing of the amyloid precursor protein (APP) by BACE-1 and c-secretase is central to the aetiology of Alzheimer's disease. Consequently, inhibition of BACE-1, a rate-limiting enzyme in the production of Ab, is an attractive therapeutic approach for the treatment of Alzheimer's disease. We have designed a selective non-peptidic BACE-1 inhibitor, GSK188909, that potently inhibits b-cleavage of APP and reduces levels of secreted and intracellular Ab in SHSY5Y cells expressing APP. In addition, we demonstrate that this compound can effectively lower brain Ab in vivo. In APP transgenic mice, acute oral administration of GSK188909 in the presence of a p-glycoprotein inhibitor to markedly enhance the exposure of GSK188909 in the brain decreases b-cleavage of APP and results in a significant reduction in the level of Ab40 and Ab42 in the brain. Encouragingly, subchronic dosing of GSK188909 in the absence of a p-glycoprotein inhibitor also lowers brain Ab. This pivotal first report of central Ab lowering, following oral administration of a BACE-1 inhibitor, supports the development of BACE-1 inhibitors for the treatment of Alzheimer's disease.

The putamen of the human striatum is a heterogeneous nucleus that contains the primary site of loss of dopamine (DA) in Parkinson's disease (PD). Furthermore, different functional domains of the putamen are heterogeneously susceptible to DA loss, and yet the dynamic regulation of extracellular DA concentration ([DA] o ) and comparison between domains has not been explored in the primate brain. In these studies, DA was measured in real time using fast-scan cyclic voltammetry at a carbon-fiber microelectrode in vitro in striatal sections from the common marmoset (Callithrix jacchus).[DA] o released by a single stimulus pulse varied threefold along a ventromedial-dorsolateral axis. DA uptake was via the DA transporter (GBR12909 sensitive, desipramine insensitive). On the basis of data modeling with simulations of Michaelis-Menten kinetics, rate maximum, V max , varied with region: both [DA] o and V max were greatest in regions most vulnerable in PD. These differences were reflected in part by regional variation in DA content. [DA] o , V max , and regional variation were two-to threefold greater than in rodent caudatoputamen.In addition, steady-state [DA] o at physiological firing rates in primate striatum was controlled by depolarization frequency, uptake, and presynaptic autoreceptors. Furthermore, regulation of [DA] o by these mechanisms differed significantly between limbic-and motor-associated domains.These data indicate interspecies heterogeneity in striatal DA dynamics that must be considered when extrapolating behavioral and drug responses from rodent to the primate brain. Moreover, the heterogeneity demonstrated within the primate putamen in the availability and dynamic regulation of DA may be central to understanding DA function in health, cocaine abuse, and disease.Key words: Parkinson's disease; basal ganglia; DA transporter; DA uptake; autoreceptor; cocaine The putamen of the primate striatum performs major sensorimotor, cognitive, and emotive functions. A central component of the basal ganglia, the putamen receives the main corticostriatal inputs from the motor, premotor, supplementary motor, and sensorimotor cortices (Kunzle, 1975(Kunzle, , 1977(Kunzle, , 1978Jones et al., 1977;Selemon and Goldman-Rakic, 1985). In turn, loss of dopaminergic innervation underlies the motor dysfunctions of Parkinson's disease (PD) (Hornykiewicz, 1966;Kish et al., 1988). Furthermore, studies using [18 F]-dopa positron emission tomography imaging, HPLC, and [ 3 H]-mazindol binding in PD and in intermediate primate 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP)-parkinsonism indicate that dopamine (DA) deinnervation follows a regionspecific pattern of vulnerability, beginning in dorsolateral putamen (Elsworth et al., 1987;Kish et al., 1988;Moratella et al., 1992;Antonini et al., 1995). The functions of the intact putamen are topographically compartmentalized along a dorsolateral-ventromedial axis (Haber and McFarland, 1999) with respect to corticostriatal (Kunzle, 1975(Kunzle, , 1977Selemon and Goldman-Rakic, 1985...

The dorsal striatum comprises a continuum of distinct functional domains, limbic, associative, and sensorimotor. In the primate it exclusively subdivides further into two nuclei, the putamen and caudate. Dopamine (DA) transmission is differentially affected between these nuclei in neurodegenerative diseases such as Parkinson's and by psychostimulants such as cocaine. Because rodent systems can offer only limited insight into DA systems of the human brain, a fuller appreciation of DA transmission and its role in dysfunction requires direct study in primates. DA behavior was explored in the major functional domains of the caudate nucleus and compared with the putamen, using fast-scan cyclic voltammetry in striatal sections from the marmoset (Callithrix jacchus). There was domain-specific variation in extracellular DA transients [i.e., concentration ([DA](o)) released by a single stimulus and the rate maximum of DA uptake, V(max)]. Across nuclei, functional rather than anatomical regions were differentiated by these dynamics. The largest, fastest DA transients were at motor-associated loci. Evoked [DA](o) at physiological frequencies was differently frequency-sensitive between functional domains but not between anatomical nuclei. In contrast, presynaptic depression was not an index of regional differentiation, recovering with similar kinetics at all loci. Within a given functional domain of dorsal striatum, the dynamics of DA release and uptake are similar for the putamen and the caudate nucleus. Conversely, distinct functional domains are defined by these DA dynamics, in a manner more marked in primates than in rodents. These data from the primate brain highlight differences in DA availability that may be central to DA function and dysfunction in the human.

No abstract

The effects of an intravitreal or subretinal injection of soluble or aggregated forms of Aβ1–42 on retinal nestin-immunoreactivity (−IR) and glial fibrillary acidic protein (GFAP)-IR in astrocytes and Müller glial cells and the integrity of the blood-retinal barrier (BRB) were tested in the in vivo rat vitreal-retinal model. Retinas were exposed for 1, 2, 3, 5 or 30 days. We present novel data demonstrating that aggregated Aβ1–42 up-regulates nestin-IR in astrocytes and Müller cells, with a graded response directly related to the length of pre-injection aggregation time. Similar results were obtained with GFAP-IR, but the signal was weaker. An intravitreal injection of aggregated Aβ1–42 led to VEGF-IR up-regulation, particularly in the GCL and to a lesser extent in the INL. VEGFR1-IR (Flt1) was also increased, particularly in Müller cells and this was accompanied by marked leakage of albumin into the retinal parenchyma of the injected eye, but not in the contralateral eye.