Premium
S5‐02‐06: The role of ApoE and ApoE receptors for synaptic dysfunction in Alzheimer's disease
Author(s) -
Herz Joachim
Publication year - 2009
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2009.05.582
Subject(s) - apolipoprotein e , long term depression , nmda receptor , neuroscience , ampa receptor , receptor , synapse , synaptic plasticity , biology , silent synapse , medicine , biochemistry , disease
Background: It has been demonstrated that APP transgenic mice with engineered disruption of Abca1 (ABCA1ko) have an increased level of amyloid plaques. In addition, Abca1ko mice have decreased levels of soluble ApoA-I and ApoE in brain whereas the level of insoluble apolipoproteins is not changed. In APP mice with global deletion of Abca1 the decrease of ApoE and ApoA-I is accompanied by an increased insoluble Amyloid beta (Ab). Our most recent experiments demonstrate that APP23 mice with one functional Abca1 allele (APP/Abca1þ/ ) have cognitive deficits when compared to APP23 with intact Abca1 (APP/Abca1wt). We have further investigated if Abca1-regulated generation of lipid-rich ApoE, not the decreased levels of ApoE and ApoA-I, is a critical mediator of Ab aggregation and behavioral deficits. Methods: To test this hypothesis we generated APP/PS1DE9 transgenic mice with global deletion of ApoE and ApoA-I genes (APP/ApoA-Iko/ApoEko) and have compared the amyloid deposition and cognitive decline in APP/ApoA-Iko/ ApoEko to those in APP/Abca1-ko and APP/Abca1wt. Results: The results of these experiments show that APP/Abca1-/mice have the highest level of amyloid deposition as well as the most prominent memory deficits. In contrast, APP/ApoA-Iko/ApoEko animals have virtually no amyloid plaques and significantly decreased insoluble Ab, but worse cognitive performance compared to APP/Abca1wt, whose memory deficits were the same as those of APP/ApoEko mice. Most surprisingly the levels of soluble Ab oligomers recognized as Ab*, were indistinguishable in APP/Abca1ko and APP/ApoA-Iko/ApoEko mice. Conclusions: The results from our study demonstrate that Abca1 and brain lipoproteins have a significant, yet not fully understood, impact on Ab aggregation and, even more, the formation of Ab oligomer structures. Considering the regulatory role of ABCA1 on ApoE and ApoA-I lipidation a prerequisite for their normal function related to brain cholesterol and phospholipid metabolism and transport, further studies will undoubtedly improve our understanding of central pathogenic mechanisms in Alzheimer Disease and will substantiate new therapeutic approaches.