Experimental neurology
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Experimental neurology · Jun 2010
ReviewBiological markers of amyloid beta-related mechanisms in Alzheimer's disease.
Recent research progress has given detailed knowledge on the molecular pathogenesis of Alzheimer's disease (AD), which has been translated into an intense, ongoing development of disease-modifying treatments. Most new drug candidates are targeted on inhibiting amyloid beta (Abeta) production and aggregation. In drug development, it is important to co-develop biomarkers for Abeta-related mechanisms to enable early diagnosis and patient stratification in clinical trials, and to serve as tools to identify and monitor the biochemical effect of the drug directly in patients. ⋯ Molecular aberrations in the AD brain are reflected in the cerebrospinal fluid (CSF). Core CSF biomarkers include Abeta isoforms (Abeta40/Abeta42), soluble APP isoforms, Abeta oligomers and beta-site APP-cleaving enzyme 1 (BACE1). This article reviews recent research advances on core candidate CSF and plasma Abeta-related biomarkers, and gives a conceptual review on how to implement biomarkers in clinical trials in AD.
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Experimental neurology · Jun 2010
ReviewTau-directed drug discovery for Alzheimer's disease and related tauopathies: a focus on tau assembly inhibitors.
The microtubule-associated protein tau forms insoluble filaments that deposit as neurofibrillary tangles (NFTs) in the brains of those with Alzheimer's disease (AD) and other related neurodegenerative disorders. The presence of both NFTs and amyloid beta (Abeta)-containing senile plaques within the brain is required to confirm the diagnosis of AD. ⋯ This trend may be changing, as there are an increasing number of research programs that are exploring ways to reduce NFTs in AD and related tauopathies. We briefly review recent advances in tau-based drug discovery, with an emphasis on the identification of compounds that inhibit the assembly of tau into multimers and fibrils.
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Experimental neurology · May 2010
ReviewThe potentiation of peripheral nerve sheaths in regeneration and repair.
Traumatic injury to the nervous system often results in life changing loss of neurological function. Spontaneous neural regeneration occurs rarely and the outcome of therapeutic intervention is most often unacceptable. An intensive effort is underway to improve methods and technologies for nervous system repair. ⋯ Experimental alteration of nerve sheath composition can also potentiate nerve and improve key features of nerve regeneration. For instance, enzymatic degradation of inhibitory chondroitin sulfate proteoglycan mimics endogenous processes that potentiate degenerated nerve and improves the outcome of direct nerve repair and grafting in animal models. This review provides a perspective of the essential role that peripheral nerve sheaths play in regulating axonal regeneration and focuses on discoveries leading to the inception and development of novel therapies for nerve repair.
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Experimental neurology · May 2010
ReviewA conditioning lesion induces changes in gene expression and axonal transport that enhance regeneration by increasing the intrinsic growth state of axons.
Injury of axons in the peripheral nervous system (PNS) induces transcription-dependent changes in gene expression and axonal transport that promote effective regeneration by increasing the intrinsic growth state of axons. Regeneration is enhanced in axons re-injured 1-2 weeks after the intrinsic growth state has been increased by such a prior conditioning lesion (CL). The intrinsic growth state does not increase after axons are injured in the mammalian central nervous system (CNS), where they lack the capacity for effective regeneration. ⋯ A CL of peripheral branches increases the intrinsic growth state of central branches in the dorsal columns of the spinal cord, enabling these axons to undergo lengthy regeneration in a segment of peripheral nerve transplanted into the spinal cord (i.e., a peripheral nerve graft). This regeneration does not occur in the absence of a CL. We will examine how changes in gene expression and axonal transport induced by a CL may promote this regeneration.