Journal of Alzheimer's Disease - Volume 46, issue 2

Authors: Zhan, Xinhua | Cox, Christopher | Ander, Bradley P. | Liu, Dazhi | Stamova, Boryana | Jin, Lee-Way | Jickling, Glen C. | Sharp, Frank R.

Article Type: Research Article

Abstract: Background: Ischemia, white matter injury, and Alzheimer’s disease (AD) pathologies often co-exist in aging brain. How one condition predisposes to, interacts with, or perhaps causes the others remains unclear. Objectives: To better understand the link between ischemia, white matter injury, and AD, adult rats were administered lipopolysaccharide (LPS) to serve as an inflammatory stimulus, and 24 h later subjected to 20-min focal cerebral ischemia (IS) followed by 30-min hypoxia (H). Methods: Myelin and axonal damage, as well as amyloid-β (Aβ) and amyloid-β protein precursor (AβPP) deposition were examined by Western blot and immunocytochemistry following LPS/IS/H. Findings …were compared to the 5XFAD mouse AD brain. Results: Myelin/axonal injury was observed bilaterally in cortex following LPS/IS/H, along with an increase in IL-1, granzyme B, and LPS. AβPP deposition was present in ischemic striatum in regions of myelin loss. Aβ1-42 and AβPP were deposited in small foci in ischemic cortex that co-localized with myelin aggregates. In the 5XFAD mouse AD model, cortical amyloid plaques also co-localized with myelin aggregates. Conclusions: LPS/IS/H produce myelin injury and plaque-like aggregates of myelin. AβPP and Aβ co-localize with these myelin aggregates. Show more

Keywords: Alzheimer’s disease, amyloid plaques, amyloid-β, amyloid-β protein precursor, hypoxia, lipopolysaccharide, myelin, myelin basic protein

DOI: 10.3233/JAD-143072

Citation: Journal of Alzheimer's Disease, vol. 46, no. 2, pp. 507-523, 2015

Authors: Starks, Erika J. | Patrick O’Grady, J. | Hoscheidt, Siobhan M. | Racine, Annie M. | Carlsson, Cynthia M. | Zetterberg, Henrik | Blennow, Kaj | Okonkwo, Ozioma C. | Puglielli, Luigi | Asthana, Sanjay | Dowling, N. Maritza | Gleason, Carey E. | Anderson, Rozalyn M. | Davenport-Sis, Nancy J. | DeRungs, LeAnn M. | Sager, Mark A. | Johnson, Sterling C. | Bendlin, Barbara B.

Article Type: Research Article

Abstract: Background: Insulin resistance (IR) is linked with the occurrence of pathological features observed in Alzheimer’s disease (AD), including neurofibrillary tangles and amyloid plaques. However, the extent to which IR is associated with AD pathology in the cognitively asymptomatic stages of preclinical AD remains unclear. Objective: To determine the extent to which IR is linked with amyloid and tau pathology in late-middle-age. Method: Cerebrospinal fluid (CSF) samples collected from 113 participants enrolled in the Wisconsin Registry for Alzheimer’s Prevention study (mean age = 60.6 years), were assayed for AD-related markers of interest: Aβ 42 , P-Tau181 , …and T-Tau. IR was determined using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Linear regression was used to test the effect of IR, and APOE ɛ 4, on tau and amyloid pathology. We hypothesized that greater IR would be associated with higher CSF P-Tau181 and T-Tau, and lower CSF Aβ 42 . Results: No significant main effects of HOMA-IR on P-Tau181 , T-Tau, or Aβ 42 were observed; however, significant interactions were observed between HOMA-IR and APOE ɛ 4 on CSF markers related to tau. Among APOE ɛ 4 carriers, higher HOMA-IR was associated with higher P-Tau181 and T-Tau. Among APOE ɛ 4 non-carriers, HOMA-IR was negatively associated with P-Tau181 and T-Tau. We found no effects of IR on Aβ 42 levels in CSF. Conclusion: IR among asymptomatic APOE ɛ 4 carriers was associated with higher P-Tau181 and T-Tau in late-middle age. The results suggest that IR may contribute to tau-related neurodegeneration in preclinical AD. The findings may have implications for developing prevention strategies aimed at modifying IR in mid-life. Show more

Keywords: Alzheimer’s disease, apolipoprotein ɛ4, cerebrospinal fluid, glucose, insulin, insulin resistance, tau protein

DOI: 10.3233/JAD-150072

Citation: Journal of Alzheimer's Disease, vol. 46, no. 2, pp. 525-533, 2015

Authors: Armbrecht, Harvey J. | Siddiqui, Akbar M. | Green, Michael | Farr, Susan A. | Kumar, Vijaya B. | Banks, William A. | Patrick, Ping | Shah, Gul N. | Morley, John E.

Article Type: Research Article

Abstract: The senescence-accelerated mouse (SAMP8) strain exhibits an age-related decrease in memory accompanied by an increase in hippocampal amyloid-β protein precursor (AβPP) and amyloid-β peptide (Aβ). We have shown that administration of an antisense oligonucleotide against the Aβ region of AβPP (AβPP antisense) reverses the memory deficits. The purpose of this study was to determine the effect of peripheral (IV) administration of AβPP antisense on hippocampal gene expression. The AβPP antisense reversed the memory deficits and altered expression of 944 hippocampal genes. Pathway analysis showed significant gene expression changes in nine pathways. These include the MAPK signaling pathway (p  = 0.0078) and …the phosphatidylinositol signaling pathway (p  = 0.043), which we have previously shown to be altered in SAMP8 mice. The changes in these pathways contributed to significant changes in the neurotropin (p  = 0.0083) and insulin signaling (p  = 0.015) pathways, which are known to be important in learning and memory. Changes in these pathways were accompanied by phosphorylation changes in the downstream target proteins p70S6K, GSK3β, ERK, and CREB. These changes in hippocampal gene expression and protein phosphorylation may suggest specific new targets for antisense therapy aimed at improving memory. Show more

Keywords: Antisense oligonucleotides, gene expression, MAPK signaling, memory loss, phosphatidylinositol signaling, SAMP8 mouse

DOI: 10.3233/JAD-142760

Citation: Journal of Alzheimer's Disease, vol. 46, no. 2, pp. 535-548, 2015

Article Type: Meeting Report

DOI: 10.3233/JAD-150271

Citation: Journal of Alzheimer's Disease, vol. 46, no. 2, pp. 549-552, 2015