Paul Mathews, PhD

Paul M. Mathews, PhD

Research Scientist
Nathan S. Kline Institute for Psychiatric Research Mathews Lab Page
Assistant Professor, Department of Psychiatry
NYU Langone Medical Center Mathews NYU Page
P: (845)398-5428 (office)
P: (845)398-5439 (lab)
F: (845)398-5422


B.S. (Medicinal Microbiology), Stanford University
Ph.D. (Biology), Johns Hopkins University
Postdoctoral Training
Cell Biology, University of Lausanne, Switzerland
Neurobiology, McLean Hospital, Harvard Medical School, Dept of Psychiatry

Research Interests

My background is in cell biology and membrane protein trafficking, so my interests in neurodegenerative processes gravitate towards understanding how alterations in vesicular trafficking and/or the trafficking of specific membrane proteins and their ligands through the multicompartment endosomal system impacts Alzheimer’s disease progression. We employ in vitro cell models as well as mouse models, such as β-amyloid depositing transgenic mice, models of Down syndrome, and mice humanized for the three human apolipoprotein E (APOE) alleles. The neuronal endosomal system is dysregulated early in sporadic AD, which we have shown can be driven by the disease-risk APOE e4 allele (APOE4) independently of the hallmark AD pathologies of β-amyloid and tau accumulation. Each of the three APOE alleles have aging-dependent effects on the endosomal system of neurons, and our goals are to identify both pathological processes and protective effects mediated during aging that can be modified within the context of individual’s APOE genotype and/or be leveraged to limit aging-driven endosomal pathway dysfunction. Additionally, the endosomal system plays a critical role in the metabolism of the amyloid precursor protein (APP) as it is trafficked from the trans-Golgi to the plasma membrane, internalized, and recycled back to the Golgi. At the plasma membrane and within early endosomes, APP can be engaged by proteolytic processes in a complex interplay between APP trafficking, compartment dwell-time and the presences and activity of specific APP-cleaving proteases. In collaboration with others in the CDR, we have shown that APP itself can modulate endosomal function through signaling mediated by the β-cleaved C-terminal fragment of APP, which is generated in early endosomes as a short transmembrane peptide. Currently we are investigating the complex signaling of this βCTF within the dynamic early endosomal system, which mediates sorting towards the lysosome as well as recycling to the plasma membrane and the trans-Golgi. Capitalizing on our prior efforts to develop tools, primarily monoclonal antibodies, and related assays such as ELISAs that allowed us to detect with high specificity and great sensitivity many of the key metabolites of APP, we are currently repurposing unique βCTF antibodies to modify βCTF function within the endosomal pathway. The laboratory’s overall goal is to integrate our understanding of genetic risk factors – such as APOE4 – endosome-signaling moieties relevant to Alzheimer’s disease – such as the βCTF of APP – and aging while developing therapeutic tools that will allow for optimal neuronal endosomal pathway functioning.


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