Hopefully, such future studies will be conducted with appropriate experimental blinding and sufficient power to ensure that the results obtained are widely reproducible. Insights into Bortezomib IC50 the mechanistic basis for the regional distribution and spread of AD pathology Classic postmortem studies have framed the characteristic progression and regional distribution of tau and A?? pathology in the brain. In AD, tau pathology characteristically spreads from the entorhinal cortex into limbic and association cortices as AD evolves [7]. Several studies that have appeared this year provide mechanistic insights into the distribution and spread of tau pathology [8,9]. The microtubule associated protein tau has traditionally been thought to be a cytoplasmic protein.

It has been known for some time that soluble tau can be detected in CSF, but its presence in a body fluid was attributed to leakage from dead or dying cells [10]. More recent data from both cell culture studies and in vitro microdialysis suggest that tau and tau aggregates can be constitutively secreted from cells [11]. Moreover, there is evidence that extracellular tau aggregates can seed intracellular aggregation. Two papers published in the last year suggest that tau secretion and subsequent seeding of aggregation can occur in vivo and account for the progression of tau pathology in vivo [8,9]. Both of these papers describe studies using transgenic mice expressing the frontotemporal dementia-associated tau P301L mutant in the entorrhinal cortex, and both demonstrated that tau pathology begins in the entorrhinal cortex in these mice but spreads along anatomically connected networks, possibly through synaptic connections.

These data are important conceptually as they provide further evidence that tau pathology in AD may spread through a prion-like conformation-dependent templating reaction mediated by release of tau aggregates from one cell and subsequent internalization by a neighbouring cell. They also provide an explanation for the potential efficacy of anti-tau immunotherapy [12]. Although it is possible that anti-tau antibodies modulate tau pathology by somehow entering neurons and altering tau aggregation, these data would suggest that some anti-tau antibodies may block spread of tau pathology from one cell to another by targeting the extracellular tau transmitted from one cell to another.

Does epigenetic modification offer new insights for developing treatment strategies? The role of epigenetic mechanisms, that is, the ability of non-genetic factors to cause genes to express themselves differently GSK-3 without changing following their underlying DNA structure, is becoming apparent in an ever increasing number of biological and medical fields and may offer insights into why therapeutic strategies targeting amyloid pathology have been unsuccessful to date.