SAP97-mediated local trafficking is altered in Alzheimer disease patients' hippocampus

Abstract

Synapse-asssociated protein-97 (SAP97) is responsible for the trafficking of both glutamate receptor subunits, GluR1 and NR2A, and ␣-secretase ADAM10 to the synaptic membrane. Here we evaluate the trafficking capability of SAP97 in Alzheimer disease (AD) patients' brain. We analyzed autoptic hippocampus and superior frontal gyrus, respectively as an affected and a less affected area, from 6 AD patients (Braak 4) and 6 healthy controls. In hippocampus, but not in superior frontal gyrus, of AD patients, ADAM10 and GluR1 synaptic membrane levels are altered while NR2A localization is not affected. Both immunoprecipitation and pull-down assays demonstrated that SAP97 failed to correctly couple to ADAM10 and GluR1, but not to NR2A. These findings not only indicate SAP97 as a point of convergence between amyloid cascade and synaptic failure in AD, but also allow a different interpretation of AD which can be now perceived as synaptic trafficking defect pathology.

Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer’s disease

“…A large increase in the amount of AP2 subunits bound to ADAM10 was observed in AD patients compared with HC ( Figure 1, B and C; α-adaptin: HC = 198.8 ± 55.8, AD = 412.5 ± 57.1, P = 0.023; β2-adaptin: HC = 227 ± 25.7, AD = 338.3 ± 39.5, P = 0.039; μ2: HC = 167.8 ± 21.5, AD = 274.8 ± 38.9, P = 0.037; AD versus HC). As previously demonstrated, the ADAM10 total levels were not affected by the group (15), and no differences were detected between HC and AD patients in α-adaptin, β2-adaptin, and μ2 subunit levels in total homogenates, suggesting that the increased association is not related to the augmented abundance of the partners ( Figure 1, B and D; α-adaptin: HC = 71.5 ± 7.8, AD = 81.7 ± 7; β2-adaptin: HC = 67.3 ± 9.1, AD = 89.5 ± 9.5; μ2: HC = 52.3 ± 3, AD = 52.8 ± 3.3; P > 0.05; AD versus HC). Moreover, we confirmed that γ-adaptin does not precipitate with ADAM10 in both HC and AD patients' hippocampus homogenate and its expression is not affected by the group (γ-adaptin: HC = 21.7 ± 3.1, AD = 20.8 ± 4.9; P > 0.05; AD versus HC).…”

“…The interaction involves the SH3 domain of SAP97 and an atypical proline-rich domain within the C-terminal region of ADAM10, and favours the forward trafficking of ADAM10 and its localization in synaptic membranes and, thereby, its APP-cleaving activity (12). The ADAM10/SAP97 interaction has been shown to be reduced in brains from AD patients (15), and the disruption of the association between SAP97 and ADAM10 in vivo using peptides leads to the generation of a nontransgenic model of the disease (16). Thus, forward trafficking and membrane insertion are crucial not only for maintaining a pool of ADAM10 at synaptic sites and for ADAM10-shedding activity, but also for healthy neuronal function.…”

Coxsackievirus Adenovirus Receptor Loss Impairs Adult Neurogenesis, Synapse Content, and Hippocampus Plasticity

“…Therefore, we assayed protein extracts from hippocampi from the Braak IV stage of patients diagnosed with AD and age-matched controls. In the hippocampi of these well characterized AD patients, the levels of several synapse proteins, including SYP and SNAP25, were not altered, demonstrating that significant synapse loss had not yet occurred (Marcello et al, 2012). Remarkably though, global CAR levels were significantly decreased already at Braak IV stage of late-onset AD (Fig.…”

“…Human brain samples were processed in accordance with European bioethics laws regarding patient information: written consent was obtained from participant. AD and control hippocampal extracts have been described previously (Marcello et al, 2012). Primary hippocampal neurons were prepared from OF1 embryonic day 18 (E18) mice embryos.…”

New approach to capture and characterize synaptic proteome

“…For example, among the cargos that we characterized, the Kif5C cargos PURα (38) and spectrin (39) have essential roles in synapse development; Kif3A cargos SAP97 (40) and RyR2 (41), and Kif5C cargos JIP-3 (42) from the hippocampus and gephyrin (43) from the PFC, are involved in Alzheimer's disease; and abnormal expression of GAP-43 (Kif5C cargo in PFC) is implicated in schizophrenia (44), suggesting the importance of kinesin cargos in psychiatric disorders.…”