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Humanin (HN) is a 24-residue peptide displaying a protective activity in vitro against a range of cytotoxic and neurotoxic insults, as well as mediating in vivo amelioration of Alzheimer disease (AD)-related memory impairment in experimental models. Published evidence suggests that the mechanisms through which HN exerts its cyto- and neuroprotective activity may include its secretion and binding to membrane-associated receptors. Here, we describe the identification of a new modulator of HN neuroprotective activity, V-set and transmembrane domain containing 2 like (VSTM2L), previously known as C20orf102. VSTM2L interacts with HN in both yeast and mammalian cells, is secreted in cultured cells, is present in serum, and is selectively expressed in the central nervous system. VSTM2L colocalizes with HN in distinct brain areas as well as in primary cultured neurons, where it plays a role in the modulation of neuronal viability. When tested in HN neuroprotection bioassays, VSTM2L acts as a strong antagonist of HN neuroprotective activity. In summary, VSTM2L is the first example of a secreted antagonist of HN and may play a role in the modulation of HN biological functions. [ABSTRACT FROM AUTHOR]

J. Neurochem. (2010) 112, 1539–1551. To investigate the role of the Wnt inhibitor Dickkopf-1 (DKK-1) in the pathophysiology of neurodegenerative diseases, we analysed DKK-1 expression and localization in transgenic mouse models expressing familial Alzheimer’s disease mutations and a frontotemporal dementia mutation. A significant increase of DKK-1 expression was found in the diseased brain areas of all transgenic lines, where it co-localized with hyperphosphorylated tau-bearing neurons. In TgCRND8 mice, DKK-1 immunoreactivity was detected in neurons surrounding amyloid deposits and within the choline acetyltransferase-positive neurons of the basal forebrain. Active glycogen synthase kinase-3 (GSK-3) was found to co-localize with DKK-1 and phospho-tau staining. Downstream to GSK-3, a significant reduction in β-catenin translocation to the nucleus, indicative of impaired Wnt signaling functions, was found as well. Cumulatively, our findings indicate that DKK-1 expression is associated with events that lead to neuronal death in neurodegenerative diseases and support a role for DKK-1 as a key mediator of neurodegeneration with therapeutic potential. [ABSTRACT FROM AUTHOR]

• Antibodies have been developed for therapeutic use in several CNS indications. • Natural barriers need to be passed for antibodies to engage their targets in the CNS. • Clinical results with the first generations of antibodies were disappointing. • Inadequate or insufficient target engagement could be the reason for clinical failures. Significant efforts have been channeled into developing antibodies for the treatment of CNS indications. Disappointment with the first generation of clinical Tau antibodies in Alzheimer's disease has highlighted the challenges in understanding whether an antibody can reach or affect the target in the compartment where it is involved in pathological processes. Here, we highlight different aspects essential for improving translatability of Tau-based immunotherapy. [ABSTRACT FROM AUTHOR]

Huntington''s Disease (HD) is a rare neurodegenerative disease caused by mutation of the huntingtin gene that results in a protein with an expanded stretch of glutamine repeats (polyQ). Knowledge of validated targets is in its infancy, and thus, traditional target-based drug discovery strategies are of limited use. Alternative approaches are needed, and early attempts were aimed at identifying molecules that inhibited the aggregation of polyQ huntingtin fragments. More recently, phenotypic assays were used to find molecules able to reverse some of the pathogenic mechanisms of HD. Such discovery strategies have an impact on the configuration of screening cascades for effective translation of drug candidates toward clinical trials. [Copyright &y& Elsevier]