Counts Lab
Lab Personnel
- Scott E. Counts, PhD, Principal Investigator
- John Beck
- Moumita Hore
- Moulika Shaik
Overview
MULTI-FUNCTIONAL microRNAS IN MCI AND RESILIENCE
Dr. Counts is a Project Leader of the NIH-funded Program Project Grant (PPG), “Neurobiology of mild cognitive impairment (MCI) in the elderly,” which has been continuously funded since 1997 and has produced over 300 papers on the molecular pathology of MCI and cognitive resilience, which refers to individuals who come to autopsy with intact cognition but who display AD pathology consistent with a diagnosis of intermediate or high likelihood of AD upon postmortem analysis.
Our current PPG goal is to understand the role of dysregulated microRNAs in MCI and resilience. MicroRNAs are small, noncoding RNAs that coordinate cellular protein expression by differentially targeting mRNAs for degradation. Notably, we have recently identified several microRNAs that simultaneously operate in multiple AD-related pathways such as tau and amyloid metabolism, synaptic and mitochondrial function, and neuroinflammation.
Our research platform begins with combined small RNA and RNA sequencing of default mode network mode (DMN, e.g., posterior cingulate cortex) tissues. The DMN is a resting-state functional connectome that mediates autobiographical and episodic memory and falters very early during the progression of AD.
Second, bioinformatic and pathway analysis of the sequencing datasets is performed by our collaborator, Dr. Christy Kelley (Arizona State University) to identify candidate multifunctional microRNAs relevant to MCI or resilient cases.
Third, upon candidate microRNA prioritization, our group collaborates with Dr. Debomoy Lahiri at the University of Indiana to perform postmortem and in vitro validation and mechanistic studies.
As representative data, please refer to the graph below, which shows that individual resilience-related microRNAs identified in posterior cingulate cortex are predicted to target networks of AD-related genes. This is a Team Science PPG endeavor that synergizes the expertise of several labs to identify novel, upstream, “multi-hit” neuroprotective microRNA pathways that can then be harnessed for preclinical experimental therapeutics.
NORADRENERGIC PATHOLOGY IN MCI AND VCID
Pontine noradrenergic locus coeruleus (LC) projection neurons mediate attention and memory, and our group was the first to demonstrate that significant LC neuron loss occurs in amnestic MCI and correlates with poorer cognitive function. Our current focus is on testing the extent to which LC degeneration promotes cognitive impairment in MCI by driving forebrain cerebrovascular dysfunction. We also apply this focus to understanding the molecular basis of VCID. Our platform approaches this goal in three ways.
First, we are using selective immunotoxins to lesion the LC in Tg344-19 AD rats, a well-characterized rodent model of AD, which also provides us with the “plus and play” ability to co-treat with validated and novel test compounds to mitigate the effects of the LC lesions. The animals are then assessed for memory function in behavioral tasks and postmortem i) neurochemical analysis, ii) evaluation of vascular (e,g., cerebral amyloid angiopathy and blood-brain barrier [BBB] permeability), and iii) AD-like pathology. We also collaborate MSU colleagues to analyze the effects of LC lesions on i) cortical perfusion and neurovascular coupling by MRI (Drs. Robert Wiseman, Dept. Physiology, and Chunqi Qian, Dept. Radiology), and ii) ex vivo vessel physiology using pressure myography (Dr. Anne Dorrance, Dept. Pharmacology and Physiology). Finally, we have been collaborating with Dr. Roxana Carare, Univ. Southampton, to investigate the role of the LC in modulating intramural periarterial drainage pathways involved on clearing amyloid and other toxins from the brain.
Second, forebrain microvessels from control and lesioned Tg344-19 AD rats¬ have recently been queried by RNA sequencing. We are currently evaluating the differentially expressed genes and pathways dysregulated in lesioned rat for i) protein expression validation and vascular cell subtype specificity, ii) validation in postmortem human tissue from MCI and early AD subjects, and iii) tractability as novel mechanisms linking LC degeneration with cerebrovascular dysfunction.
Third, validated and prioritized target genes and pathways will be tested for their role in vascular dysfunction and/or protection via mechanistic assays in 3D cell culture models.
Please refer to the poster below, recently presented at VasCog 2025. The Counts lab has been at the forefront of understanding how LC degeneration impacts MCI and AD clinical symptomology. Targeting noradrenergic mechanistic pathways in microvessels may allow for more comprehensive disease modification in MCI and AD by reducing vascular contributions to cognitive impairment.
