, 2010). In a manner similar to the infamous prions, misfolded oligomers composed by diverse proteins can act as a template to induce the conversion of natively folded proteins, propagating the abnormalities to other cells, tissues, and organs. In the case of tau pathology, the current study by de Calignon et al., in addition to various recent reports from other groups (Clavaguera et al., 2009, Frost

et al., 2009, Guo and Lee, 2011 and Nonaka et al., 2010), indicates that misfolding and aggregation of tau may start in a restricted area of the brain and from there spread toward other regions through synaptic connections, leading to a progressive amplification of the damage and expansion throughout the brain. Many open questions regarding this prion-like phenomenon of spreading of tau misfolding still need to be addressed, including the following four points. (1) What are the factors and mechanisms responsible for the formation of the first Microbiology inhibitor misfolded tau seeds? In the present study, pathology

was initiated by artificial expression of a human mutant version of the tau gene in a defined brain area. In the study by Clavaguera and colleagues (2009), the seeds were introduced by direct intracerebral injection of brain homogenates containing tau aggregates. It is possible to envision at least three different ways in which the initial seeds may arise. First, seeds may be formed spontaneously in a particular area of the brain, perhaps PI3K inhibitor as a consequence of somatic mutations, transcriptional/translational errors, defects of the proteostasis machinery, or tissue injury (e.g., brain trauma or subclinical stroke), all of which are probably more frequent during aging. Second, the initial seeds may be acquired exogenously through an “infection-like” process of exposure to preformed aggregates. In prion diseases, transmission between individuals can occur through medical practices (e.g., blood transfusion, organ transplants, and use of materials or surgical tools contaminated with prions), consumption of food from animals carrying misfolded prions, or Thalidomide vertical transmission (Will, 2003). Third, misfolded aggregates composed of one protein may interact

and promote the aggregation of another protein by a phenomenon known as cross-seeding. Evidence for this process has been found for several PMDs, using animal models, in vitro systems, and human epidemiological analysis (see Morales et al., 2009 and references therein). It is also possible that non-disease-associated aggregates (so-called functional amyloids) may also induce misfolding of disease-related proteins through cross-seeding (Johan et al., 1998). (2) What are the mechanisms responsible for the transference of tau seeds between cells? Studies with cellular models of tau and α-synuclein suggest that intracellular aggregates gain access to the extracellular space either by secretion or by damage of the host cell (Guo and Lee, 2011 and Nonaka et al.