The Proteome of the Dentate Terminal Zone of the Perforant Path Indicates Presynaptic Impairment in Alzheimer Disease
Molecular & Cellular Proteomics. 2020-01-01; 19(1): 128-141
DOI: 10.1074/mcp.ra119.001737
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Haytural H(1), Mermelekas G(2), Emre C(3), Nigam SM(4), Carroll SL(5), Winblad
B(6), Bogdanovic N(7), Barthet G(8), Granholm AC(9), Orre LM(2), Tjernberg LO(3),
Frykman S(3).
Author information:
(1)Division of Neurogeriatrics, Center for Alzheimer Research, Department of
Neurobiology, Care Sciences and Society, Karolinska Institutet, Solna, Sweden.
Electronic address: .
(2)Department of Oncology-Pathology, Science for Life Laboratory, Karolinska
Institutet, Stockholm, Sweden.
(3)Division of Neurogeriatrics, Center for Alzheimer Research, Department of
Neurobiology, Care Sciences and Society, Karolinska Institutet, Solna, Sweden.
(4)Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
(5)Department of Pathology and Laboratory Medicine, Medical University of South
Carolina, Charleston, South Carolina.
(6)Division of Neurogeriatrics, Center for Alzheimer Research, Department of
Neurobiology, Care Sciences and Society, Karolinska Institutet, Solna, Sweden;
Karolinska University Hospital, Theme Aging, Stockholm, Sweden.
(7)Karolinska University Hospital, Theme Aging, Stockholm, Sweden; Division of
Clinical geriatrics, Center for Alzheimer Research, Department of Neurobiology,
Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.
(8)Interdisciplinary Institute for Neuroscience, CNRS UMR, Bordeaux, France;
University of Bordeaux, Bordeaux, France.
(9)Division of Neurogeriatrics, Center for Alzheimer Research, Department of
Neurobiology, Care Sciences and Society, Karolinska Institutet, Solna, Sweden;
Knoebel Institute for Healthy Aging, University of Denver, Denver, Colorado.
Synaptic dysfunction is an early pathogenic event in Alzheimer disease (AD) that
contributes to network disturbances and cognitive decline. Some synapses are more
vulnerable than others, including the synapses of the perforant path, which
provides the main excitatory input to the hippocampus. To elucidate the molecular
mechanisms underlying the dysfunction of these synapses, we performed an
explorative proteomic study of the dentate terminal zone of the perforant path.
The outer two-thirds of the molecular layer of the dentate gyrus, where the
perforant path synapses are located, was microdissected from five subjects with
AD and five controls. The microdissected tissues were dissolved and digested by
trypsin. Peptides from each sample were labeled with different isobaric tags,
pooled together and pre-fractionated into 72 fractions by high-resolution
isoelectric focusing. Each fraction was then analyzed by liquid
chromatography-mass spectrometry. We quantified the relative expression levels of
7322 proteins, whereof 724 showed significantly altered levels in AD. Our
comprehensive data analysis using enrichment and pathway analyses strongly
indicated that presynaptic signaling, such as exocytosis and synaptic vesicle
cycle processes, is severely disturbed in this area in AD, whereas postsynaptic
proteins remained unchanged. Among the significantly altered proteins, we
selected three of the most downregulated synaptic proteins; complexin-1,
complexin-2 and synaptogyrin-1, for further validation, using a new cohort
consisting of six AD and eight control cases. Semi-quantitative analysis of
immunohistochemical staining confirmed decreased levels of complexin-1,
complexin-2 and synaptogyrin-1 in the outer two-thirds of the molecular layer of
the dentate gyrus in AD. Our in-depth proteomic analysis provides extensive
knowledge on the potential molecular mechanism underlying synaptic dysfunction
related to AD and supports that presynaptic alterations are more important than
postsynaptic changes in early stages of the disease. The specific synaptic
proteins identified could potentially be targeted to halt synaptic dysfunction in
AD.
© 2020 Haytural et al.