Involvement of insulin receptor substrates in cognitive impairment and Alzheimer’s disease

Type 2 diabetes—associated with impaired insulin/insulin-like growth factor-1 (IGF1) signaling (IIS)—is a risk factor for cognitive impairment and dementia including Alzheimer’s disease (AD). The insulin receptor substrate (IRS) proteins are major components of IIS, which transmit upstream signals via the insulin receptor and/or IGF1 receptor to multiple intracellular signaling pathways, including AKT/protein kinase B and extracellular-signal-regulated kinase cascades. Of the four IRS proteins in mammals, IRS1 and IRS2 play key roles in regulating growth and survival, metabolism, and aging. Meanwhile, the roles of IRS1 and IRS2 in the central nervous system with respect to cognitive abilities remain to be clarified. In contrast to IRS2 in peripheral tissues, inactivation of neural IRS2 exerts beneficial effects, resulting in the reduction of amyloid β accumulation and premature mortality in AD mouse models. On the other hand, the increased phosphorylation of IRS1 at several serine sites is observed in the brains from patients with AD and animal models of AD or cognitive impairment induced by type 2 diabetes. However, these serine sites are also activated in a mouse model of type 2 diabetes, in which the diabetes drug metformin improves memory impairment. Because IRS1 and IRS2 signaling pathways are regulated through complex mechanisms including positive and negative feedback loops, whether the elevated phosphorylation of IRS1 at specific serine sites found in AD brains is a primary response to cognitive dysfunction remains unknown. Here, we examine the associations between IRS1/IRS2-mediated signaling in the central nervous system and cognitive decline

Amyloid β-protein oligomers upregulate the β-secretase, BACE1, through a post-translational mechanism involving its altered subcellular distribution in neurons

Quantification of fluorescence intensities in axons and dendrites. After double immunofluorescent staining of primary neurons with anti-BACE1 (green) and anti-MAP2 (red) antibodies, specimens were examined under a LSM780 microscope. BACE1 fluorescence intensities along MAP2-positive dendrites (red line) and MAP2-negative axons (blue line) were quantified as described in Methods. Scale bar = 10 μm. (PDF 66 kb

Magnetic Properties of 1:2 Mixed Cobalt(II) Salicylaldehyde Schiff-Base Complexes with Pyridine Ligands Carrying High-Spin Carbenes (<i>S</i>_car = 2/2, 4/2, 6/2, and 8/2) in Dilute Frozen Solutions: Role of Organic Spin in Heterospin Single-Molecule Magnets

The 1:2 mixtures of Co­(<i>p</i>-tolsal)₂, <i>p</i>-tolsal = <i>N</i>-<i>p</i>-tolylsalicylideniminato, and diazo-pyridine ligands, <b>DXpy</b>; <b>X</b> = <b>1</b>,<b> 2</b>,<b> 3l</b>,<b> 3b</b>, and <b>4</b>, in MTHF solutions were irradiated at cryogenic temperature to form the corresponding 1:2 cobalt–carbene complexes Co­(<i>p</i>-tolsal)₂(<b>CXpy</b>)₂, with <i>S</i>_total = 5/2, 9/2, 13/2, 13/2, and 17/2, respectively. The resulting Co­(<i>p</i>-tolsal)₂(<b>CXpy</b>)₂, <b>X</b> = <b>1</b>,<b> 2</b>,<b> 3l</b>,<b> 3b</b>, and <b>4</b>, showed magnetic behaviors characteristic of heterospin single-molecule magnets with effective activation barriers, <i>U</i>_eff/<i>k</i>_B, of 40, 65, 73, 72, and 74 K, for reorientation of the magnetic moment and temperature-dependent hysteresis loops with a coercive force, <i>H</i>_c, of ∼0, 6.2, 10, 6.5, and 9.0 kOe at 1.9 K, respectively. The relaxation times, τ_Q, due to a quantum tunneling of magnetization (QTM) were estimated to be 1.6 s for Co­(<i>p</i>-tolsal)₂(<b>C1py</b>)₂, ∼2.0 × 10³ s for Co­(<i>p</i>-tolsal)₂(<b>C2py</b>)₂, and >10⁵ s for Co­(<i>p</i>-tolsal)₂(<b>CXpy</b>)₂; <b>X</b> = <b>3b</b>,<b> 3l</b>, and <b>4</b>. In heterospin complexes, organic spins, carbenes interacted with the cobalt ion to suppress the QTM pathway, and the τ_Q value increased with increasing the <i>S</i>_total values