%0 Journal Article %J J Alzheimers Dis %D 2016 %T Impaired Autophagy in APOE4 Astrocytes. %A Simonovitch, Shira %A Schmukler, Eran %A Bespalko, Alina %A Iram, Tal %A Frenkel, Dan %A Holtzman, David M %A Masliah, Eliezer %A Michaelson, Danny M %A Pinkas-Kramarski, Ronit %K Amyloid beta-Peptides %K Animals %K Apolipoprotein E3 %K Apolipoprotein E4 %K Astrocytes %K Autophagy %K Brain %K Cells, Cultured %K Central Nervous System Agents %K Chloroquine %K Disease Models, Animal %K Humans %K Mice, Transgenic %K Plaque, Amyloid %K Sirolimus %K Time Factors %X

Alzheimer's disease (AD) is the most prevalent form of dementia in elderly. Genetic studies revealed allelic segregation of the apolipoprotein E (ApoE) gene in sporadic AD and in families with higher risk of AD. The mechanisms underlying the pathological effects of ApoE4 are not yet entirely clear. Several studies indicate that autophagy, which plays an important role in degradation pathways of proteins, organelles and protein aggregates, may be impaired in AD. In the present study, we investigated the effects of ApoE4 versus the ApoE3 isoform on the process of autophagy in mouse-derived astrocytes. The results obtained reveal that under several autophagy-inducing conditions, astrocytes expressing ApoE4 exhibit lower autophagic flux compared to astrocytes expressing ApoE3. Using an in situ model, we examined the role of autophagy and the effects thereon of ApoE4 in the elimination of Aβ plaques from isolated brain sections of transgenic 5xFAD mice. This revealed that ApoE4 astrocytes eliminate Aβ plaques less effectively than the corresponding ApoE3 astrocytes. Additional experiments showed that the autophagy inducer, rapamycin, enhances Aβ plaque degradation by ApoE4 astrocytes whereas the autophagy inhibitor, chloroquine, blocks Aβ plaque degradation by ApoE3 astrocytes. Taken together, these findings show that ApoE4 impairs autophagy in astrocyte cultures and that this effect is associated with reduced capacity to clear Aβ plaques. This suggests that impaired autophagy may play a role in mediating the pathological effects of ApoE4 in AD.

%B J Alzheimers Dis %V 51 %P 915-27 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923027?dopt=Abstract %R 10.3233/JAD-151101 %0 Journal Article %J Sci Transl Med %D 2011 %T Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. %A Castellano, Joseph M %A Kim, Jungsu %A Stewart, Floy R %A Jiang, Hong %A DeMattos, Ronald B %A Patterson, Bruce W %A Fagan, Anne M %A Morris, John C %A Mawuenyega, Kwasi G %A Cruchaga, Carlos %A Goate, Alison M %A Bales, Kelly R %A Paul, Steven M %A Bateman, Randall J %A Holtzman, David M %K Adult %K Aged %K Alleles %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Apolipoprotein E4 %K Biomarkers %K Brain %K Female %K Genotype %K Humans %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Microdialysis %K Middle Aged %K Protein Isoforms %X

The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease (AD). The APOE ε4 allele markedly increases AD risk and decreases age of onset, likely through its strong effect on the accumulation of amyloid-β (Aβ) peptide. In contrast, the APOE ε2 allele appears to decrease AD risk. Most rare, early-onset forms of familial AD are caused by autosomal dominant mutations that often lead to overproduction of Aβ(42) peptide. However, the mechanism by which APOE alleles differentially modulate Aβ accumulation in sporadic, late-onset AD is less clear. In a cohort of cognitively normal individuals, we report that reliable molecular and neuroimaging biomarkers of cerebral Aβ deposition vary in an apoE isoform-dependent manner. We hypothesized that human apoE isoforms differentially affect Aβ clearance or synthesis in vivo, resulting in an apoE isoform-dependent pattern of Aβ accumulation later in life. Performing in vivo microdialysis in a mouse model of Aβ-amyloidosis expressing human apoE isoforms (PDAPP/TRE), we find that the concentration and clearance of soluble Aβ in the brain interstitial fluid depends on the isoform of apoE expressed. This pattern parallels the extent of Aβ deposition observed in aged PDAPP/TRE mice. ApoE isoform-dependent differences in soluble Aβ metabolism are observed not only in aged but also in young PDAPP/TRE mice well before the onset of Aβ deposition in amyloid plaques in the brain. Additionally, amyloidogenic processing of amyloid precursor protein and Aβ synthesis, as assessed by in vivo stable isotopic labeling kinetics, do not vary according to apoE isoform in young PDAPP/TRE mice. Our results suggest that APOE alleles contribute to AD risk by differentially regulating clearance of Aβ from the brain, suggesting that Aβ clearance pathways may be useful therapeutic targets for AD prevention.

%B Sci Transl Med %V 3 %P 89ra57 %8 2011 Jun 29 %G eng %N 89 %1 http://www.ncbi.nlm.nih.gov/pubmed/21715678?dopt=Abstract %R 10.1126/scitranslmed.3002156 %0 Journal Article %J Nat Neurosci %D 2011 %T Neuronal activity regulates the regional vulnerability to amyloid-β deposition. %A Bero, Adam W %A Yan, Ping %A Roh, Jee Hoon %A Cirrito, John R %A Stewart, Floy R %A Raichle, Marcus E %A Lee, Jin-Moo %A Holtzman, David M %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Cerebral Cortex %K Disease Models, Animal %K Extracellular Fluid %K Female %K Lactic Acid %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Microdialysis %K Neurons %K Plaque, Amyloid %K Sensory Deprivation %K Somatosensory Cortex %X

Amyloid-β (Aβ) plaque deposition in specific brain regions is a pathological hallmark of Alzheimer's disease. However, the mechanism underlying the regional vulnerability to Aβ deposition in Alzheimer's disease is unknown. Herein, we provide evidence that endogenous neuronal activity regulates the regional concentration of interstitial fluid (ISF) Aβ, which drives local Aβ aggregation. Using in vivo microdialysis, we show that ISF Aβ concentrations in several brain regions of APP transgenic mice before plaque deposition were commensurate with the degree of subsequent plaque deposition and with the concentration of lactate, a marker of neuronal activity. Furthermore, unilateral vibrissal stimulation increased ISF Aβ, and unilateral vibrissal deprivation decreased ISF Aβ and lactate, in contralateral barrel cortex. Long-term unilateral vibrissal deprivation decreased amyloid plaque formation and growth. Our results suggest a mechanism to account for the vulnerability of specific brain regions to Aβ deposition in Alzheimer's disease.

%B Nat Neurosci %V 14 %P 750-6 %8 2011 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/21532579?dopt=Abstract %R 10.1038/nn.2801