The therapeutic importance of understanding mechanisms of neuronal cell death in neurodegenerative disease

Despite major advances in our understanding of the initiating factors that trigger many neurodegenerative disorders, to date, no novel disease-modifying therapies have been shown to provide significant benefit for patients who suffer from these devastating disorders. As most neurodegenerative disorders are late-onset, slowly progressive, and appear to have long relatively asymptomatic prodromal phases, it is possible that therapies optimally targeting the triggers of these disorders may have limited benefit when treatment is initiated in the symptomatic patient. Such therapies may work in the prodromal phase, or when given prophylactically, but in the symptomatic patient there simply may be too much damage to the neuronal networks to restore functionality by reducing or even eliminating the primary stressor. As functional neuronal demise and overt neuronal death are almost certainly the key factors that mediate the functional impairment, it is clear that preventing neuronal death and dysfunction will have a huge clinical benefit. Unfortunately, we lack a detailed understanding of neuronal death pathways in almost all neurodegenerative disorders. To rationally develop new disease modifying therapies that target steps in the degenerative cascade downstream of the disease trigger will require a number of factors. First, we need to refocus our basic research efforts on identifying the precise steps in the pathological cascade that lead to neuronal death in each neurodegenerative disease and, if possible, determine the relative placement of those events within a potentially very complex cascade. Second, we will need to determine which of these steps are potentially targetable. Finally, we will need to develop novel therapies that interfere with these steps and demonstrate that such therapies alone, or in combination with therapies that target the trigger of these devastating diseases, have clinical benefit

Intramembrane-cleaving aspartic proteases and disease: presenilins, signal peptide peptidase and their homologs

Recent studies demonstrate that presenilins (PSs) and signal peptide peptidase (SPP) are members of a novel protease family of integral membrane proteins that may utilize a catalytic mechanism similar to classic aspartic proteases such as pepsin, renin and cathepsin D. The defining features of the PSs and SPP are their ability to cleave substrate polypeptides within a transmembrane region, the presence of two active site aspartate residues in adjacent membrane-spanning regions and a conserved PAL motif near their COOH-terminus. PSs appear to be the catalytic subunit of multiprotein complexes that possess γ-secretase activity. Because this activity generates the amyloid β peptide (Aβ) deposited in the brain of patients with Alzheimer's disease (AD), PSs are considered therapeutic targets in AD. In contrast to PSs that are not active unless part of a larger complex, SPP does not appear to require protein co-factors. Because of its requirement for hepatitis C virus maturation and a possible immune modulatory role, SPP is also considered a potential therapeutic target. Four additional PS/SPP homologs have been identified in humans; yet, their functions have not been elucidated. Herein, we will review the recent advances in our understanding of the PS/SPP family of proteases as well as discuss aspects of intramembrane cleavage that are not well understoo

Zoom in on neurodegeneration

Despite the existence of several scientific journals that publish research papers and reviews related to neurodegenerative diseases, a journal specifically devoted to the molecular and cellular aspects of disease mechanisms is lacking. Molecular Neurodegeneration is an open-access, peer-reviewed, online journal created to publish original research articles that address i) the mechanisms of neurodegeneration at the cellular, subcellular and molecular levels and ii) potential therapeutic interventions for neurodegenerative diseases. Through publication of reviews, editorial commentaries, and meeting reports, Molecular Neurodegeneration will also provide a forum to enhance the exchange of ideas and promote debate that is essential for scientific progress. Molecular Neurodegeneration will enable scientists to rapidly communicate their important research discoveries to their colleagues around the world

Biochemical detection of Aβ isoforms: implications for pathogenesis, diagnosis, and treatment of Alzheimer’s disease

AbstractPrior to the identification of the various abnormal proteins deposited as fibrillar aggregates in the Alzheimer’s disease (AD) brain, there was tremendous controversy over the importance of the various lesions with respect to primacy in the pathology of AD. Nevertheless, based on analogy to systemic amyloidosis, many investigators believed that the amyloid deposits in AD played a causal role and that characterization of these deposits would hold the key to understanding this complex disease. Indeed, in retrospect, it was the initial biochemical purifications of the ∼4 kDa amyloid β-peptide (Aβ) from amyloid deposits in the mid 1980s that launched a new era of AD research (Glenner and Wong, Biochem. Biophys. Res. Commun. 122 (1984) 1121–1135; Wong et al., Proc. Natl. Acad Sci. USA 82 (1985) 8729–8732; and Masters et al., Proc. Natl. Acad Sci. USA 82 (1985) 4245–4249). Subsequent studies of the biology of Aβ together with genetic studies of AD have all supported the hypothesis that altered Aβ metabolism leading to aggregation plays a causal role in AD. Although there remains controversy as to whether Aβ deposited as classic amyloid or a smaller, aggregated, form causes AD, the relevance of studying the amyloid deposits has certainly been proven. Despite the significant advances in our understanding of the role of Aβ in AD pathogenesis, many important aspects of Aβ biology remain a mystery. This review will highlight those aspects of Aβ biology that have led to our increased understanding of the pathogenesis of AD as well as areas which warrant additional study

Hippocampal expression of murine TNFα results in attenuation of amyloid deposition in vivo

Fibrillar amyloid β (fAβ) peptide is the major component of Aβ plaques in the brains of Alzheimer's disease (AD) patients. Inflammatory mediators have previously been proposed to be drivers of Aβ pathology in AD patients by increasing amyloidogenic processing of APP and promoting Aβ accumulation, but recent data have shown that expression of various inflammatory cytokines attenuates Aβ pathology in mouse models. In an effort to further study the role of different inflammatory cytokines on Aβ pathology in vivo, we explored the effect of murine Tumor Necrosis Factor α (mTNFα) in regulating Aβ accumulation. Recombinant adeno-associated virus serotype 1 (AAV2/1) mediated expression of mTNFα in the hippocampus of 4 month old APP transgenic TgCRND8 mice resulted in significant reduction in hippocampal Aβ burden. No changes in APP levels or APP processing were observed in either mTNFα expressing APP transgenic mice or in non-transgenic littermates. Analysis of Aβ plaque burden in mTNFα expressing mice showed that even after substantial reduction compared to EGFP expressing age-matched controls, the Aβ plaque burden levels of the former do not decrease to the levels of 4 month old unmanipulated mice. Taken together, our data suggests that proinflammatory cytokine expression induced robust glial activation can attenuate plaque deposition. Whether such an enhanced microglial response actually clears preexisting deposits without causing bystander neurotoxicity remains an open question

Notch signals in the endothelium and cancer "stem-like" cells: opportunities for cancer therapy

Anti-angiogenesis agents and the identification of cancer stem-like cells (CSC) are opening new avenues for targeted cancer therapy. Recent evidence indicates that angiogenesis regulatory pathways and developmental pathways that control CSC fate are intimately connected, and that endothelial cells are a key component of the CSC niche. Numerous anti-angiogenic therapies developed so far target the VEGF pathway. However, VEGF-targeted therapy is hindered by clinical resistance and side effects, and new approaches are needed. One such approach may be direct targeting of tumor endothelial cell fate determination. Interfering with tumor endothelial cells growth and survival could inhibit not only angiogenesis but also the self-replication of CSC, which relies on signals from surrounding endothelial cells in the tumor microenvironment. The Notch pathway is central to controlling cell fate both during angiogenesis and in CSC from several tumors. A number of investigational Notch inhibitors are being developed. Understanding how Notch interacts with other factors that control endothelial cell functions and angiogenesis in cancers could pave the way to innovative therapeutic strategies that simultaneously target angiogenesis and CSC