We hypothesize that neurodegenerative diseases progress via prion-like mechanisms accompanied by poorly reversible templated protein misfolding, and that antibodies are well suited to specifically bind to misfolded proteins while sparing the normal isoforms from autoimmune recognition. We have applied these understandings to develop novel therapeutics for amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). Misfolding and aggregation of the enzyme Cu/Zn superoxide dismutase (SOD1) has been implicated in the pathogenesis of sporadic and familial ALS. We have shown that expression of G127X and G85R, natural FALS SOD1 mutants, can induce misfolding of natively-structured SOD1 in human mesenchymal and neural cell lines, as determined by molecular surface immunoreactivity with misfolding-specific monoclonal antibodies (mAbs) and acquisition of protease sensitivity (Grad et al, PNAS 2011). Consistent with a "species barrier," wtSOD1 conversion is abolished by expression of human G127X SOD1 in mouse cell lines, and in human cells of a G127X in which the Trp32 is substituted for murine Ser32. G127X, wtSOD1 and SOD1 fragments are detectable in supernatants of G127X transfected cells, and naïve cells incubated in the presence of this medium undergo intracellular SOD1 misfolding which can be "transmitted" indefinitely from culture to culture by conditioned supernatant (Grad et al, PNAS 2014). Incubation of G127X SOD1-transfected conditioned media with SOD1 antibodies, but not DNase, abrogates this activity. These data are consistent with the notion that human SOD1 can participate in a template-directed misfolding cascade which can be transmitted intercellularly, providing a possible molecular mechanism for the propagation of ALS through the neuroaxis. For AD, our identification of an Aβ oligomer-specific epitope is supporting the development of immunotherapies which are targeted to neutralize their neurotoxicity and fibril-seeding properties.