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Neurodegenerative diseases lead to significant morbidity and mortality. Although medical care for other disorders (e.g., cardiovascular disease and cancer) has improved, neurodegenerative diseases have become more prevalent as the population ages. Understanding of the scientific underpinnings of neurodegenerative diseases has advanced greatly over the last thirty years. However, with a few exceptions, very few effective treatments are available to delay the onset or affect the course of these diseases. This Forum convened leaders in the field of neurodegeneration from different disciplines and tasked them with defining areas in need of more attention. A time frame of 5–20 years was the goal within which to develop more effective diagnostics and treatments. This chapter identifies eight key areas to address. With significant progress in each area, substantial changes in the diagnosis and treatment of neurodegenerative diseases should be possible over the next twenty years. Given the current cost of these diseases to society and the increase in their prevalence with no additional progress, a major worldwide effort should be made to address these issues immediately.

Classically, research into human disease tends to be done in a top- down or bottom- up manner, starting from symptoms or genes, respectively. While bottom-up approaches may work well in oncology, and might advance understanding of monogenic neuropsy- chiatric diseases, successful application for complex, multifactorial disorders is more difficult and has resulted in many translational failures. This chapter investigates the existing obstacles and explores options to overcome them. Complex diseases need to be dissected into measureable, manageable factors and investigated in a comparable, compatible assembly of model systems to test hypotheses, concepts, and ultimately drug candidates or other therapeutic interventions. While some of these factors might best be investigated top down, a bottom-up approach might be more effective for oth- ers. Both approaches may only be successful up to a specific point. Thus, the two must be linked and a bidirectional approach pursued. Inclusion of patients is essential as are behavioral readouts, since disease-associated dysfunctions or symptoms are often behavioral in nature. To connect models and humans, behavioral readouts need ide- ally to be linked to evolutionary conserved neural substrates. Some anchor points al- ready exist and new promising ones, such as induced pluripotent stem cells (iPSCs), are emerging. Recent developments may speed up translation of research into clinical applications (e.g., faster drug screens in a patient-specific manner). When positioning different models, it is important to characterize their predictive power diligently, to em- phasize their scientific rigor, and to not overstate their application potential. Finally, to effect faster transition from research to clinical applications, organizational structures are needed to foster interdisciplinary research and collaborations between academia and industry. A “ third space” concept is proposed to conduct early proof of principle studies (Phase 0 and

Background: Microglia, the resident immune cells of the brain, have been implicated in brain injury and various neurological disorders. However, their precise roles in different pathophysiological situations remain enigmatic and may range from detrimental to protective. Targeting the delivery of biologically active compounds to microglia could help elucidate these roles and facilitate the therapeutic modulation of microglial functions in neurological diseases.Methods: Here we employ primary cell cultures and stereotaxic injections into mouse brain to investigate the cell type specific localization of semiconductor quantum dots (QDs) in vitro and in vivo. Two potential receptors for QDs are identified using pharmacological inhibitors and neutralizing antibodies.Results: In mixed primary cortical cultures, QDs were selectively taken up by microglia; this uptake was decreased by inhibitors of clathrin-dependent endocytosis, implicating the endosomal pathway as the major route of entry for QDs into microglia. Furthermore, inhibiting mannose receptors and macrophage scavenger receptors blocked the uptake of QDs by microglia, indicating that QD uptake occurs through microglia-specific receptor endocytosis. When injected into the brain, QDs were taken up primarily by microglia and with high efficiency. In primary cortical cultures, QDs conjugated to the toxin saporin depleted microglia in mixed primary cortical cultures, protecting neurons in these cultures against amyloid beta-induced neurotoxicity.Conclusions: These findings demonstrate that QDs can be used to specifically label and modulate microglia in primary cortical cultures and in brain and may allow for the selective delivery of therapeutic agents to these cells. © 2012 Minami et al; licensee BioMed Central Ltd.