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How to improve R&D productivity: the pharmaceutical industry's grand challenge
A detailed analysis based on comprehensive, recent, industry-wide data is presented to identify the relative contributions of each of the steps in the drug discovery and development process to overall R&D productivity and propose specific strategies that could have the most substantial impact in improving R &D productivity. Expand
Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor.
Two metabolites of the steroid hormones progesterone and deoxycorticosterone are potent barbiturate-like ligands of the gamma-aminobutyric acid (GABA) receptor-chloride ion channel complex and potentiated the inhibitory actions of GABA in cultured rat hippocampal and spinal cord neurons, which may explain the ability of certain steroid hormones to rapidly alter neuronal excitability. Expand
Human apoE Isoforms Differentially Regulate Brain Amyloid-β Peptide Clearance
New light is shed on how apoE4 is implicated in AD and the Aβ clearance pathway is highlighted as a new target for developing drugs to slow or even halt the accumulation of amyloid plaques in patients with AD. Expand
Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein.
SorLA acts as a sorting receptor that protects APP from processing into Abeta and thereby reduces the burden of amyloidogenic peptide formation and may increase Abeta production and plaque formation and promote spontaneous AD. Expand
Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease.
It is found that a monoclonal antibody (m266) directed against the central domain of A beta was able to bind and completely sequester plasma A beta in transgenic mouse models of Alzheimer's disease. Expand
Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer's disease
Although peripheral administration of m266 to PDAPP mice markedly reduces Aβ deposition, m266 did not bind to Aβ deposits in the brain, and m266 appears to reduce brain Aβ burden by altering CNS and plasma Aβ clearance. Expand
P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model.
The data establish a direct link between Pgp and Abeta metabolism in vivo and suggest that Pgp activity at the BBB could affect risk for developing AD as well as provide a novel diagnostic and therapeutic target. Expand
Immunization reverses memory deficits without reducing brain Aβ burden in Alzheimer's disease model
We have previously shown that chronic treatment with the monoclonal antibody m266, which is specific for amyloid β-peptide (Aβ), increases plasma concentrations of Aβ and reduces Aβ burden in theExpand
Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease.
The data demonstrate a critical and isoform-specific role for apoE in neuritic plaque formation, a pathological hallmark of AD. Expand
Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo.
It is demonstrated that Abeta levels in the brain interstitial fluid are dynamically and directly influenced by synaptic activity on a timescale of minutes to hours, suggesting that synaptic activity may modulate a neurodegenerative disease process, in this case by influencing Abeta metabolism and ultimately region-specific Abeta deposition. Expand