Accumulation of intraneuronal A beta correlates with ApoE4 genotype

作者：Christensen Ditte Z; Schneider Axmann Thomas; Lucassen Paul J; Bayer Thomas A; Wirths Oliver^*

来源：Acta Neuropathologica, 2010, 119(5): 555-566.

DOI：10.1007/s00401-010-0666-1

• Intracellular Abeta
• Intraneuronal Abeta
• Alzheimer
• Microwave
• Amyloid
• Astrocyte
• ApoE
• Formic acid
• Heat
• Antigen retrieval

In contrast to extracellular plaque and intracellular tangle pathology, the presence and relevance of intraneuronal A beta in Alzheimer's disease (AD) is still a matter of debate. Human brain tissue offers technical challenges such as post-mortem delay and uneven or prolonged tissue fixation that might affect immunohistochemical staining. In addition, previous studies on intracellular A beta accumulation in human brain often used antibodies targeting the C-terminus of A beta and differed strongly in the pretreatments used. To overcome these inconsistencies, we performed extensive parametrical testing using a highly specific N-terminal A beta antibody detecting the aspartate at position 1, before developing an optimal staining protocol for intraneuronal A beta detection in paraffin-embedded sections from AD patients. To rule out that this antibody also detects the beta-cleaved APP C-terminal fragment (beta-CTF, C99) bearing the same epitope, paraffin-sections of transgenic mice overexpressing the C99-fragment were stained without any evidence for cross-reactivity in our staining protocol. The staining intensity of intraneuronal A beta in cortex and hippocampal tissue of 10 controls and 20 sporadic AD cases was then correlated to patient data including sex, Braak stage, plaque load, and apolipoprotein E (ApoE) genotype. In particular, the presence of one or two ApoE4 alleles strongly correlated with an increased accumulation of intraneuronal A beta peptides. Given that ApoE4 is a major genetic risk factor for AD and is involved in neuronal cholesterol transport, it is tempting to speculate that perturbed intracellular trafficking is involved in the increased intraneuronal A beta aggregation in AD.

• 出版日期2010-5