The main goal of the Ginsberg laboratory is to understand the molecular and cellular substrates that regulate selective vulnerability of neurons to degeneration.
A multidisciplinary approach of state-of-the-art multi-‘omics approaches, including microaspiration of select neuronal types through laser capture microdissection and single population RNA-sequencing along with protein-protein interaction (PPI) network-based methods combined with immunohistochemical and cell biological techniques is utilized as part of the experimental design. Particular emphasis is placed upon analyzing the interactomes of individual neuronal populations as a means of understanding the complex cascade of cellular events that occurs under pathologic conditions such as aging, the Alzheimer’s disease (AD) spectrum from no cognitive impairment (NCI) to mild cognitive impairment (MCI) to AD, Alzheimer’s disease related dementias (ADRD), metabolic syndrome/insulin resistance, and Down syndrome (DS). The Ginsberg lab employs well characterized postmortem human brain tissues as well as relevant animal and cellular models of neurodegenerative disorders. These include mouse models of amyloid overexpression, tauopathy, and DS/AD.
Dr. Ginsberg’s underlying hypothesis is that individual cell types are likely to have unique patterns of gene and protein expression under normative conditions that are altered in pathological states, which drives subsequent neurodegeneration. Indeed, the molecular and cellular basis of why certain neuronal populations are vulnerable to neurodegeneration, often termed “selective vulnerability”, can be elucidated by discrete cell analysis more readily than by utilizing regional and total brain preparations.
The septohippocampal connectome and the neocortical default mode network (DMN), key brain circuits critical for learning and memory and executive function, respectively, are a focus of research. Emphasis is placed on identifying mechanisms that underlie changes within specific cell types, including cholinergic basal forebrain (CBF) neurons, hippocampal CA1 & CA3 pyramidal neurons, neocortical layer III and layer V pyramidal neurons, dentate gyrus granule cells, and entorhinal cortex stellate cells.
Research Achievements
Frontal cortex pyramidal neuron expression profiles differentiate the prodromal stage from progressive degeneration across the AD spectrum.
Postmortem single cell gene expression analyses in CBF neurons demonstrates downregulation of nerve growth factor receptor TrkA, BDNF receptor TrkB, and neurotrophin-3 receptor TrkC, but not the pan-nerve growth factor receptor p75 in MCI and AD.
We identifiedd a shift in the expression of 3-repeat tau (3Rtau) relative to 4-repeat tau (4Rtau) within individual CBF neurons and CA1 pyramidal neurons in MCI and AD.
Analysis of frontal cortex layer III and V pyramidal neurons reveals a neurodegenerative phenotype in individuals with DS that extends beyond triplicated genes.
microRNA (miRNA) dysregulation within vulnerable DMN hubs differentiates cognitive resilience, MCI, and AD.
Aging, rather than genotype, is the principal contributor to differential gene expression within targeted replacement APOE2, APOE3, and APOE4 mouse brain.
Assessment of hippocampal pyramidal neurons and entorhinal cortex stellate cells in mouse models of AD and DS (Tg2576 mouse and Ts65Dn mouse) following calorie restriction and maternal choline supplementation (MCS) reveals pathway-driven benefits.
We demonstrate MCS in a mouse model of DS/AD generates unique expression profile mosaics within three hippocampal excitatory neuronal populations.
MCS rescues early endosome pathology in basal forebrain cholinergic neurons in an established murine model of DS/AD.
Current Endeavors
Expression profiling of neocortical pyramidal neurons throughout the DMN across the AD spectrum (NCI, MCI, and AD) using brain tissues from the Rush Religious Orders Study (RROS) cohort.
Expression profiling of hippocampal and basal forebrain circuits at time points before and following cholinergic neurodegeneration a mouse model of DS/AD (Ts65Dn mice).
Determining molecular and cellular substrates of PPI network dysfunction within the DMN during AD/ADRD onset and progression.
Evaluating postmortem human formalin fixed paraffin embedded frontal cortex tissue for profiling layer III and layer V pyramidal neurons via digital spatial profiling (DSP).
Future Endeavors
Critically evaluating post-translational modification (PTMs) as encoders that reprogram chaperones into epichaperomes for aberrant network control in AD/ADRD.
Evaluating molecular and cellular substrates of superior cognitive performance (SCP) versus normal cognitive performance (NCP) in very old adults.
Employing dysfunctional Protein-Protein Interactome (dfPPI), a platform for systems-level PPI dysfunction investigation across the AD spectrum.
Assessing whether AD/ADRD has origins in early life via a perturbed microbiome.
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