Preferential accumulation of amyloid-beta in presynaptic glutamatergic terminals (VGluT1 and VGluT2) in Alzheimer's disease cortex

NEUROBIOLOGY OF DISEASE

卷:45

Article

Sokolow, Sophie^1,2,3  Luu, Sanh H.¹  Nandy, Karabi^1,4  Miller, Carol A.^5,6,7  Vinters, Harry V.⁸  Poon, Wayne W.⁹  Gylys, Karen H.^1,2,3 

[1] Univ Calif Los Angeles, Sch Nursing, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, Ctr Adv Gerontol Nursing Sci, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, Dept Biostat, Sch Publ Hlth, Los Angeles, CA 90095 USA

[5] Keck USC Sch Med, Dept Pathol, Los Angeles, CA 90033 USA

[6] Keck USC Sch Med, Dept Neurol, Los Angeles, CA 90033 USA

[7] Keck USC Sch Med, Dept Program Neurosci, Los Angeles, CA 90033 USA

[8] Univ Calif Los Angeles, Sch Med, Dept Pathol & Lab Med & Neurol, Los Angeles, CA 90095 USA

[9] Univ Calif Irvine, Inst Memory Impairments & Neurol Disorders, Irvine, CA 92697 USA

关键词: Amyloid-beta;    Glutamate;    Synaptosome;    Alzheimer's disease;    VGLUT;   

DOI  :  10.1016/j.nbd.2011.08.027

来源: Elsevier

【 摘 要 】

Amyloid-beta (A beta) is thought to play a central role in synaptic dysfunction (e.g. neurotransmitter release) and synapse loss. Glutamatergic dysfunction is involved in the pathology of Alzheimer's disease (AD) and perhaps plays a central role in age-related cognitive impairment. Yet, it is largely unknown whether A beta accumulates in excitatory boutons. To assess the possibility that glutamatergic terminals are lost in AD patients, control and AD synaptosomes were immunolabeled for the most abundant vesicular glutamate transporters (VGluT1 and VGluT2) and quantified by flow cytometry and immunoblot methods. In post-mortem parietal cortex from aged control subjects, glutamatergic boutons are fairly abundant as approximately 40% were immunoreactive for VGluT1 (37%) and VGluT2 (39%). However, the levels of these specific markers of glutamatergic synapses were not significantly different among control and AD cases. To test the hypothesis that A beta is associated with excitatory terminals. AD synaptosomes were double-labeled for A beta and for VGluT1 and VGluT2, and analyzed by flow cytometry and confocal microscopy. Our study demonstrated that A beta immunoreactivity (IR) was present in glutamatergic terminals of AD patients. Quantification of A beta and VGluT1 in a large population of glutamatergic nerve terminals was performed by flow cytometry, showing that 42% of VGluT1 synaptosomes were immunoreactive for A beta compared to 9% of VGluT1 synaptosomes lacking A beta-IR. Percentage of VGluT2 synaptosomes immunoreactive for A beta (21%) was significantly higher than VGluT2 synaptosomes lacking A beta-IR (9%). Moreover, A beta preferentially affects VGluT1 (42% positive) compared to VGluT2 terminals (21%). These data represent the first evidence of high levels of A beta in excitatory boutons in AD cortex and support the hypothesis that A beta may play a role in modulating glutamate transmission in AD terminals. (C) 2011 Elsevier Inc. All rights reserved.

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