Inhibitory synapse loss and accumulation of amyloid beta in inhibitory presynaptic terminals in Alzheimer's disease

被引：41

作者：

Kurucu, Hatice ^{[1
,2
]}

Colom-Cadena, Marti ^{[1
,2
]}

Davies, Caitlin ^{[1
,2
]}

Wilkins, Lewis ^{[1
,2
]}

King, Declan ^{[1
,2
]}

Rose, Jamie ^{[1
,2
]}

Tzioras, Makis ^{[1
,2
]}

Tulloch, Jane H. ^{[1
,2
]}

Smith, Colin ^{[3
,4
]}

Spires-Jones, Tara L. ^{[1
,2
]}

机构：

[1] Univ Edinburgh, Ctr Discovery Brain Sci, 1 George Sq, Edinburgh EH8 9JZ, Midlothian, Scotland

[2] UK Dementia Res Inst, Edinburgh, Midlothian, Scotland

[3] Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland

[4] Univ Edinburgh, Sudden Death Brain Bank, Edinburgh, Midlothian, Scotland

来源：

EUROPEAN JOURNAL OF NEUROLOGY | 2022年 / 29卷 / 05期

基金：

英国惠康基金; 欧盟地平线“2020”; 英国医学研究理事会;

关键词：

Alzheimer; amyloid; inhibitory; synapse; TAU; MODEL; CORTEX; HIPPOCAMPUS; DISRUPTION; PATHOLOGY; DEFICITS; CELLS;

D O I：

10.1111/ene.15043

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Background and purpose Synapse degeneration in Alzheimer's disease (AD) correlates strongly with cognitive decline. There is well-established excitatory synapse loss in AD with known contributions of pathological amyloid beta (A beta) to excitatory synapse dysfunction and loss. Despite clear changes in circuit excitability in AD and model systems, relatively little is known about pathology in inhibitory synapses. Methods Here human postmortem brain samples (n = 5 control, 10 AD cases) from temporal and occipital cortices were examined to investigate whether inhibitory synapses and neurons are lost in AD and whether A beta may contribute to inhibitory synapse degeneration. Inhibitory neurons were counted in all six cortical layers using stereology software, and array tomography was used to examine synapse density and the accumulation of A beta in synaptic terminals. Results Differing inhibitory neuron densities were observed in the different cortical layers. The highest inhibitory neuron density was observed in layer 4 in both brain regions and the visual cortex had a higher inhibitory neuron density than the temporal cortex. There was significantly lower inhibitory neuron density in AD than in control cases in all six cortical layers. High-resolution array tomography imaging revealed plaque-associated loss of inhibitory synapses and accumulation of A beta in a small subset of inhibitory presynaptic terminals with the most accumulation near amyloid plaques. Conclusions Inhibitory neuron and synapse loss in AD may contribute to disrupted excitatory/inhibitory balance and cognitive decline. Future work is warranted to determine whether targeting inhibitory synapse loss could be a useful therapeutic strategy.

引用

页码：1311 / 1323

页数：13

共 42 条

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