Current Alzheimer Research - Volume 4, Issue 5, 2007

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A number of factors limit the therapeutic application of neurotrophin proteins, such as nerve growth factor (NGF) and brain-derived growth factor (BDNF), for Alzheimer's and other neurodegenerative diseases. These factors include unfavorable pharmacological properties typical of proteins and the pleiotropic effects mediated by protein-ligand interactions with p75NTR, Trk, and sortilin neurotrophin receptors. Targeted modul Read More

NAP (NAPVSIPQ), derived from activity-dependent neuroprotective protein (ADNP) provides neuroprotection in vitro and in vivo against a wide variety of neurotoxic substances. To further understand the mechanism by which NAP provides broad neuroprotection it was essential to find NAP's binding partners. Previous results, using affinity chromatography coupled with mass spectrometry, identified tubulin, the subunit protein Read More

Confronting the efficacy of a regenerative therapeutic is the degenerative environment that is characterized by neuronal loss, physical plague and glial scar barriers and inflammation. But perhaps more fundamental from a regenerative perspective, are changes in the biochemical milieu of steroid and peptide growth factors, cytokines and neurotransmitter systems. Data from multiple levels of analysis indicate that gonadal Read More

The progressive memory loss observed in Alzheimer's disease (AD) is accompanied by an increase in the levels of amyloid-β peptide (Aβ) and a block of synaptic plasticity. Both synaptic plasticity and memory require changes in the expression of synaptic proteins such as the activity-regulated cytoskeleton-associated protein, Arc (also termed Arg3.1). Using a model of synaptic plasticity in which BDNF increases Arc ex Read More

Traditionally, drug design programs are focused on optimizing the specificity of lead compounds against a carefully selected drug target. Disappointingly, this approach to discover a “magic bullet” drug has not met with the expected success for CNS disorders. Transcriptomics and proteomic profiling of neurodegenerative diseases have indicated that they are poly-etiological in origin and that the processes leading t Read More

As the major genetic risk factor for Alzheimer's disease, the apolipoprotein (apo) E4 isoform is a promising therapeutic target. ApoE4 likely contributes to Alzheimer's disease pathology by interacting with multiple factors through various pathways. Interactions with the amyloid β peptide and the amyloid cascade, for example, may lead to cognitive decline and neurodegeneration. Alternatively, apoE4 might act independe Read More

While much of the focus on Alzheimer's disease therapeutics has been directed at beta-amyloid peptide or at cholinergic synaptic transmission, recent data suggest that targeting signal transduction by the amyloid precursor protein (APP) itself may be an alternative approach with significant potential [1]. Here we discuss the possibility that APPmediated signal transduction, downstream from amyloid-beta peptide production it Read More

The pathological aggregation of tau into paired helical filaments is a hallmark of several neurodegenerative diseases, including Alzheimer's disease. We have generated cell models of tau aggregation in order to study mechanisms involving abnormal changes of tau. In the cell models the repeat domain of tau (tauRD) and some of its variants are expressed in a regulated fashion, e.g. the 4-repeat domain of tau with the wild-type Read More

Cyclin-dependent kinase 5 (cdk5) is a member of the serine-threonine kinase family of cyclin-dependent kinases. This family is known for its role in the cell cycle, but cdk5 differs due to its interaction with activators p35 or p39, both abundant in post-mitotic neurons. Cdk5 is not known to have a role in cell cycle regulation at all, but is known to be an important modulator of neuronal activity. Cdk5 has been an attractive target for Read More

Background: Increasing basic science and clinical evidence implicates inflammatory processes and resulting glial activation in the pathogenesis of Alzheimer's Disease. Excess TNF-alpha, a cytokine with pleotropic effects in the CNS, has been suggested to be involved in the pathogenesis of AD. In addition to its pro-inflammatory effects, TNF-alpha affects synaptic transmission; and glutamate, NMDA, and amyloid pathways. More Read More

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Since the discovery that mutations of alpha-synuclein (AS) gene are responsible for rare forms of familiar Parkinson's disease this synaptic protein attracted increased interest. AS is the main constituent of Lewy bodies. In spite the physiological function is still unclear there is an ongoing discussion if over-expression is already dangerous, or if toxicity is subjected to oligomers, protofibrilles or mature aggregates. The fact t Read More

Amyloid β-derived diffusible ligands (ADDLs) comprise the neurotoxic subset of soluble Aβ1-42 oligomers, now widely considered to be the molecular cause of memory malfunction and neurodegeneration in Alzheimer's disease (AD). We have developed a screening cascade which identifies small molecule modulators of ADDL-mediated neurotoxicity. The primary screen involves a fluorescence resonance energy tra Read More

Pathophysiologic hypotheses for Alzheimer's disease (AD) are centered on the role of the amyloid plaque Aβ peptide and the mechanism of its derivation from the amyloid precursor protein (APP). As part of the disease process, an aberrant axonal sprouting response is known to occur near Aβ deposits. A Nogo to Nogo-66 receptor (NgR) pathway contributes to determining the ability of adult CNS axons to extend after traum Read More

γ-Secretase is responsible for the final cut of the amyloid β-peptide (Aβ) precursor (APP) to produce the Aβ peptide implicated the pathogenesis of Alzheimer's disease (AD). Thus, this protease is a top target for the development of AD therapeutics. γ-Secretase is a complex of four different integral membrane proteins, with the multi-pass presenilin being the catalytic component of a novel intramembrane-cleaving aspartyl p Read More

Drug discovery is a complex and costly endeavor, requiring multidisciplinary know-how, interdisciplinary collaboration, tenacity, and a bit of luck. For these reasons, the search for new chemical agents to treat human disease has traditionally been undertaken only within the walls of industry. While the pharmaceutical industry is often successful where it focuses its attention, it generally focuses only on those areas that are allo Read More

The M1 muscarinic receptor (M1 mAChR), preserved in Alzheimer's disease (AD), is a pivotal target that links major hallmarks of AD, e.g. cholinergic deficiency, cognitive dysfunctions, β-amyloid (Aβ) and tau pathologies. Some muscarinic agonists, while effective in AD, had limited clinical value due to adverse effects and lack of M1 selectivity. The M1 selective muscarinic agonists AF102B [Cevimeline], AF150(S) and AF267B - i) el Read More

The receptor for advanced glycation end products (RAGE) binds amyloid peptides with high affinity. Soluble RAGE-like peptides and Aβ-like peptides occur in relatively high concentrations in the circulation of individuals with Alzheimer's disease. Protein complexes with epitopes for both Aβ and RAGE are also present. At physiological concentrations, forms of Aβ have different, but relatively low potencies as cytotoxicants in neura Read More