, 2001; Morris et al., 2011; Sydow et al., 2011). Now, it appears that its role may be more dynamic, possibly participating Selleckchem RG-7204 in intracellular signal transduction, among other roles. Importantly, tau is highly susceptible to hyperphosphorylation and the formation of intracellular NFTs, both of which are hallmark neuropathologies that critically promote the damage observed in AD and TBI (McKee et al., 2009; Morris et al., 2011). ApoE4 has been shown to directly

alter microtubule structure and to stimulate tau hyperphosphorylation and NFT formation (Huang, 2010; Huang and Mucke, 2012). Exposure of neuronal cultures to exogenous apoE4-lipid complexes caused significant cytoskeletal disruption and impaired neurite outgrowth compared with apoE3-containing complexes (Bellosta et al., 1995; Nathan et al., 1994; Nathan et al., 1995). ApoE4-treated Neuro-2a cells also had fewer intracellular microtubules, as identified by immunocytochemical localization of β-tubulin and by electron microscopy (Nathan et al., 1995), and these effects were associated with

impaired neurite outgrowth in apoE4-treated cells. These results were replicated in apoE3- or apoE4-transfected Neuro-2a cells expressing nanogram quantities of apoE (Bellosta et al., 1995). Increased tau Trichostatin A research buy phosphorylation has been observed in transgenic mice expressing apoE4 in neurons, but not in those expressing apoE4 in astrocytes, suggesting a cellular source-dependent effect of apoE4 on tau phosphorylation (Harris et al., 2003; Tesseur et al., 2000), occurring in parallel with the generation

of apoE fragments in neurons whatever (Andrews-Zwilling et al., 2010; Harris et al., 2003). There is evidence that apoE4 stimulates tau phosphorylation by activating the extracellular signal-regulated protein kinase pathway in the hippocampus (Harris et al., 2004a), although other signaling pathways may also be involved. Intraneuronal phospho-tau inclusions are prominent in the hippocampus and form NFT-like structures composed of apoE4, phospho-tau, and neurofilaments; by electron microscopy, these inclusions are visualized as tightly packed, straight filaments that closely associate with mitochondria (Harris et al., 2003). In addition to such insights into the cell biological impacts of apoE fragments, transgenic animal experiments are uncovering how this neurotoxicity at the cellular level corresponds to neuronal function and behavior. The expression of truncated apoE4 in transgenic mice provides insights into how and where the fragments cause neurotoxicity. Transgenic mice expressing a variant of apoE4 that lacks the C-terminal 27 amino acids (apoE4[1–272]), driven by the Thy1.2 promoter, had significant hippocampal neurodegeneration and neuronal loss (Harris et al., 2003). However, not every fragment of apoE is toxic, because expression of apoE4(1–240)—the form lacking the lipid-binding region—was not found to trigger hippocampal neurodegeneration.