, 1995; McCarron et al., 1999; Slooter et al., 1997), frontotemporal dementia (Agosta et al., 2009), and Parkinson’s disease (Harhangi et al., 2000; Li et al., 2004; Martinez et al., 2005; Parsian et al., 2002). Furthermore, apoE4 is not rare—approximately 25% of all individuals are carriers of this allele—making the potential detrimental effects of apoE4 expression all too common. Indeed, the apoE4 allele is heavily enriched in AD patients, with 65%–80% of all AD patients carrying at least one copy

(Farrer et al., 1997). The neuropathological effects of apoE4—the least stable of the three isoforms and the most tightly associated with AD—are myriad and include Temozolomide clinical trial the following (for review, see Huang, 2010; Kim et al., 2009; Mahley et al., 2006): (1) impaired neurite outgrowth; (2) cytoskeletal disruption and hyperphosphorylation of tau; (3) mitochondrial dysfunction in neurons, including altered membrane

potential, reduced mitochondrial motility, and decreased mitochondrial respiratory enzyme levels and activity; (4) impaired synaptogenesis; (5) increased amyloid β (Aβ) production; (6) increased lysosomal Ruxolitinib cost leakage and apoptosis in neurons; (7) brain neuropathology and impaired learning and memory in mice; and (8) altered Aβ peptide clearance and/or deposition. The premise of this review is that the structural differences among the apoE isoforms determine their roles in the Cell press onset and progression of AD and other neurodegenerative diseases and that modulation of the abnormal structure of apoE4—by converting it to a more apoE3-like (or apoE2-like) structure—will reverse the apoE4-associated detrimental effects in the central nervous system (Mahley and Huang, 2012). First, however, we discuss how apoE may indirectly impact neuropathology in AD through modulation of Aβ metabolism, before moving on to present the apoE hypothesis more fully and the most recent evidence describing the

direct effects of apoE (apoE4 > apoE3 > apoE2) in the pathogenesis of neurodegenerative disorders. The amyloid hypothesis focuses on the effects of the Aβ peptide and its different assemblies in causing neuropathology, disrupting synaptic connections and forming plaques (Hardy, 2006; Palop et al., 2006; Palop and Mucke, 2010; Selkoe, 2011). Importantly, it is established that there are apoE isoform-specific effects on the Aβ pathway (Huang and Mucke, 2012; Kim et al., 2009; Selkoe, 2011) and that apoE4 expression is associated with a significant increase in amyloid plaques at earlier ages compared with apoE3 or apoE2. Furthermore, apoE4 is known to impair Aβ clearance (Bien-Ly et al., 2011; Castellano et al., 2011; Deane et al., 2008; Kim et al., 2011) and accelerate amyloid synthesis (Ye et al., 2005), as well as amyloid fibril formation and deposition (Bales et al., 1999; Bien-Ly et al., 2011; Sanan et al., 1994; Wisniewski et al., 1995).