A novel structure associated with aging is augmented in the DPP6-KO mouse brain
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RESEARCH
A novel structure associated with aging is augmented in the DPP6‑KO mouse brain Lin Lin1†, Ronald S. Petralia2†, Ross Lake3, Ya‑Xian Wang2 and Dax A. Hoffman1*
Abstract In addition to its role as an auxiliary subunit of A-type voltage-gated K+ channels, we have previously reported that the sin‑ gle 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 develop‑ ment 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. Elec‑ tron microscopy revealed that these structures are abnormal, enlarged presynaptic swellings filled with mainly fibrous mate‑ rial 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. Keywords: DPP6, Alzheimer’s disease, Aging dementia, Presynaptic terminals
Introduction 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]. We previously reported a surprising role for DPP6 in hippocampal synaptic development and function that is apparently independent of Kv4.2 [36, 37]. Clinically, the DPP6 gene has been associated with numerous intellectual and neurodevelopmental disorders [6, 17, 33, 41, 43, 47, 53, 55, 56]. An important recent study showed *Correspondence: [email protected] † Lin Lin and Ronald S. Petralia contributed equally to this work. 1 Molecular Neurophysiology and Biophysics Section, Program in Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 35 Lincoln Drive, MSC 3715, Building 35, Room 3C‑905, Bethesda, MD 20892‑3715, USA Full list of author information is available at the end of the article
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 pati
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