TaubCONNECT Research Perspectives

AN NIA-FUNDED ALZHEIMER'S DISEASE RESEARCH CENTER

Columbia University
Irving Medical Center
Neurological Institute

710 West 168th Street, 3rd floor
(212) 305-1818

TaubCONNECT Research Perspective:
June 2024

View 2024 - 2021 Archive || 2020 Archive || 2019 Archive || 2018 Archive || 2017 and Earlier Archive

1: ZCCHC17 Knockdown Phenocopies Alzheimer's Disease-Related Loss of Synaptic Proteins and Hyperexcitability

2: Design and Methods of the Early Age-Related Hearing Loss Investigation Randomized Controlled Trial

ZCCHC17 Knockdown Phenocopies Alzheimer's Disease-Related Loss of Synaptic Proteins and Hyperexcitability

Andrew F. Teich, MD, PhD

Synaptic dysfunction is a critical event in Alzheimer’s disease (AD) pathogenesis and synaptic loss correlates strongly with pre-mortem cognitive status. These structural changes are accompanied by large-scale dysregulation of synaptic gene expression in AD brain tissue, and these findings have been replicated in recent gene expression studies. Several therapeutic strategies based on rescuing synaptic dysfunction are currently being pursued, and the molecular basis for synaptic dysfunction in AD remains an outstanding question for the field.

Our group previously identified ZCCHC17 using a bioinformatic screen as a candidate driver of synaptic dysfunction in AD, and predicted that its activity is reduced in AD, leading to dysregulation of synaptic gene expression. Prior to our group’s interest in ZCCHC17, its function in the brain was unexplored, although it had been shown to have roles in both mRNA and rRNA processing in other tissues. After identifying ZCCHC17 as a candidate driver of synaptic dysfunction, we showed that ZCCHC17 protein is expressed in neurons and declines in AD brain tissue before significant gliosis or neuronal loss, and knockdown of ZCCHC17 in rat neuronal cultures leads to dysregulation of a wide range of genes, including synaptic genes. More recently, we have shown that ZCCHC17 regulates neuronal RNA splicing using human iPSC-derived neurons, and loss of ZCCHC17 may explain a portion of splicing abnormalities in AD brain tissue. Further, we have shown that CNS ZCCHC17 expression predicts cognitive resilience in the setting of AD pathology, and support for ZCCHC17 activity may therefore represent a therapeutic strategy. All of this suggests that ZCCHC17 is integral for normal neuronal functioning. However, the proteomic and electrophysiologic consequences of ZCCHC17 knockdown have not previously been explored in neurons.

In Cortese et al., recently published in the Journal of Neuropathology & Experimental Neurology, we evaluate the functional consequences of reduced ZCCHC17 expression in primary cortical cultures. Consistent with ZCCHC17’s predicted role as a master regulator of synaptic genes, we find that ZCCHC17 knockdown leads to a loss of synaptic protein expression using a range of markers. Patch recording of neurons shows that loss of ZCCHC17 significantly disrupts the E/I balance of neurotransmission and favors excitatory-dominant synaptic activity, as measured by an increase in spontaneous excitatory post synaptic currents (sEPSCs) and action potential firing rate and a decrease in spontaneous inhibitory post synaptic currents (sIPSCs). We are the first to assess the functional consequences of reduced ZCCHC17 expression in neurons, and conclude that ZCCHC17 is necessary to maintain synaptic protein expression and proper E/I balance of neurotransmission, and that loss of ZCCHC17 function may contribute to hyperexcitability in AD.

Andrew F. Teich, MD, PhD
Associate Professor of Pathology and Cell Biology (in Neurology)
aft25@cumc.columbia.edu

^ top

Design and Methods of the Early Age-Related Hearing Loss Investigation Randomized Controlled Trial

Justin S. Golub, MD, MS

Age-related hearing loss, the third most common chronic condition in later life, is associated with cognitive impairment and dementia. This finding has recently been extended by our research team to early age-related hearing loss (borderline-to-moderate in severity), which is rarely treated with hearing aids. A prominent 2020 Lancet Commissions report estimated that eliminating age-related hearing loss could be associated with an 8% reduction in new dementia cases, at least as much as well-established risk factors. Yet, the vast majority of those with hearing loss are not treated with hearing aids. One recent randomized controlled trial, called ACHIEVE, made headlines after older adults at risk for dementia had slower cognitive decline over three years if they wore hearing aids. However, there are few other high quality trials, and ACHIEVE focused only on older adults with more advanced hearing loss.

Together with Taub faculty members Dr. James Noble (Neurology) and Terry Goldberg (Psychiatry), we are conducting a new randomized controlled trial called EARHLI: Early Age-Related Hearing Loss Investigation. As recently reported in Otology & Neurotology, EARHLI focuses on early age-related hearing loss in middle and early older age, a critical time for dementia prevention. We will enroll 150 individuals aged 55-75 years old with a small degree of hearing loss and memory trouble. We will then randomize them to receive hearing aids or a health education program. Over a period of a year, we will examine cognition, socialization, and functional magnetic resonance imaging (MRI). Participants in the health education program will get hearing aids at the study end. All participants who complete the study will be allowed to keep a pair of high-end custom hearing aids. EARHLI will provide valuable information on how to improve brain health in older adults with early age-related hearing loss. Please contact us if you or someone you know may be interested in participating.

Justin S. Golub, MD, MS
Associate Professor of Otolaryngology/Head and Neck Surgery
jg3629@cumc.columbia.edu

Contact Us

630 West 168th Street
P&S Box 16
New York, NY 10032
Phone: 212 305-1818
Fax: 212 342-2849
Email: taubinstitute@columbia.edu

Brain Donation

Our ability to understand Alzheimer's disease is dependent upon studying brain tissue.

For more information, please contact Donovan Laing at (212) 305-9086 dal2190@cumc.columbia.edu

Featured Research

News

This website uses cookies as well as similar tools and technologies to understand visitors' experiences. By continuing to use this website, you consent to Columbia University's usage of cookies and similar technologies, in accordance with the Columbia University Website Cookie Notice.

Columbia University Irving Medical Center Neurological Institute

TaubCONNECT Research Perspective: June 2024