Abstract
In addition to its role as an auxiliary subunit of A-type voltage-gated K+ channels, we have previously reported that the single transmembrane protein Dipeptidyl Peptidase Like 6 (DPP6) impacts neuronal and synaptic development. DPP6-KO mice are impaired in hippocampal-dependent learning and memory and exhibit smaller brain size. Using immunofluorescence and electron microscopy, we report here a novel structure in hippocampal area CA1 that was significantly more prevalent in aging DPP6-KO mice compared to WT mice of the same age and that these structures were observed earlier in development in DPP6-KO mice. These novel structures appeared as clusters of large puncta that colocalized NeuN, synaptophysin, and chromogranin A. They also partially labeled for MAP2, and with synapsin-1 and VGluT1 labeling on their periphery. Electron microscopy revealed that these structures are abnormal, enlarged presynaptic swellings filled with mainly fibrous material with occasional peripheral, presynaptic active zones forming synapses. Immunofluorescence imaging then showed that a number of markers for aging and especially Alzheimer’s disease were found as higher levels in these novel structures in aging DPP6-KO mice compared to WT. Together these results indicate that aging DPP6-KO mice have increased numbers of novel, abnormal presynaptic structures associated with several markers of Alzheimer’s disease.
Highlights
Dipeptidyl Peptidase Like 6 (DPP6) is a type II single pass transmembrane protein expressed in brain [35, 64], and well known as an auxiliary subunit of the Kv4 family of voltage-gated K + channels [45], which play a crucial role in neuronal excitability and plasticity [23, 65]
Our findings demonstrate that DPP6, in addition to its effects on early synapse development appears to be important for the maintenance of synaptic function during aging as its loss leads to an increase in abnormal synaptic structures associated with physical and biochemical markers for dementia
A novel structure in aging mice develops earlier and is more abundant in the DPP6‐KO During the performance of Immunofluorescence (IF) staining with NeuN antibody to characterize the neurons in the hippocampus, of 12-month DPP6-KO and corresponding WT mice, we noted clusters of large puncta with NeuN labeling in the CA1 region of DPP6-KO mice (Fig. 1A–C)
Summary
DPP6 is a type II single pass transmembrane protein expressed in brain [35, 64], and well known as an auxiliary subunit of the Kv4 family of voltage-gated K + channels [45], which play a crucial role in neuronal excitability and plasticity [23, 65]. DPP6 to be a novel gene in dementia, finding enhanced rare variants and nonsense, frameshift and missense mutations in early Alzheimer’s disease (AD) and frontotemporal dementia patient cohorts [9]. Another finding by Zelaya et al [77] demonstrated an olfactory progressive proteome modulation in AD, which shows olfactory dysfunction in up to 90% of patients. They report a specific late reduction of DPP6 in the olfactory bulb of patients with AD Overall, these findings provided basic information for understanding possible roles of DPP6 in aging and the pathophysiology of diseases such as AD/dementia
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