43 research outputs found
Receptor-Associated Protein (RAP) Plays a Central Role in Modulating Aβ Deposition in APP/PS1 Transgenic Mice
BACKGROUND: Receptor associated protein (RAP) functions in the endoplasmic reticulum (ER) to assist in the maturation of several membrane receptor proteins, including low density lipoprotein receptor-related protein (LRP) and lipoprotein receptor 11 (SorLA/LR11). Previous studies in cell and mouse model systems have demonstrated that these proteins play roles in the metabolism of the amyloid precursor protein (APP), including processes involved in the generation, catabolism and deposition of beta-amyloid (Abeta) peptides. METHODOLOGY/PRINCIPAL FINDINGS: Mice transgenic for mutant APPswe and mutant presenilin 1 (PS1dE9) were mated to mice with homozygous deletion of RAP. Unexpectedly, mice that were homozygous null for RAP and transgenic for APPswe/PS1dE9 showed high post-natal mortality, necessitating a shift in focus to examine the levels of amyloid deposition in APPswe/PS1dE9 that were hemizygous null for RAP. Immunoblot analysis confirmed 50% reductions in the levels of RAP with modest reductions in the levels of proteins dependent upon RAP for maturation [LRP trend towards a 20% reduction ; SorLA/LR11 statistically significant 15% reduction (p<0.05)]. Changes in the levels of these proteins in the brains of [APPswe/PS1dE9](+/-)/RAP(+/-) mice correlated with 30-40% increases in amyloid deposition by 9 months of age. CONCLUSIONS/SIGNIFICANCE: Partial reductions in the ER chaperone RAP enhance amyloid deposition in the APPswe/PS1dE9 model of Alzheimer amyloidosis. Partial reductions in RAP also affect the maturation of LRP and SorLA/LR11, which are each involved in several different aspects of APP processing and Abeta catabolism. Together, these findings suggest a central role for RAP in Alzheimer amyloidogenesis
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Using memories to support the self in Alzheimer's disease
The impact of memory loss on the self in Alzheimer's disease (AD) is poorly understood. Previous research is mixed on whether episodic or semantic memories are most important for supporting identity. The present study examined autobiographical memories cued by self-images (e.g., I am a father) and non-self-related cues in 16 AD patients and 29 healthy older adults. The AD group generated fewer self-images and memories compared to controls, but demonstrated similar temporal organization of self-cued memories. In both groups, self-images were supported by semantic memories that were temporally clustered around times of identity-formation. These self-supporting memories are proposed to form a scaffold to support the self and may persist the longest in AD, as opposed to memories from early adulthood per se. In both AD and control groups, self-images cued more semantic memories than non-self-relevant cues, further suggesting that semantic autobiographical memories play a fundamental role in supporting the self. These findings demonstrate that the self remains largely intact in AD, in spite of severe episodic memory deficits and global cognitive decline. In later stages of the disease, these self-supporting memories could provide effective tools for reminiscence therapy