YAAKOV STERN, PHD
Professor of Neuropsychology

The RANN study is designed to explore the neural basis of cognitive aging. A primary goal is to identify age-related changes in fMRI activation patterns underlying four key cognitive processes – vocabulary, processing speed, episodic memory, and reasoning. Many other brain measures are also being explored. Over 400 healthy adults aged 20 – 80 were enrolled and we are currently conducting the five-year follow-up. All undergo an extensive cognitive evaluation and imaging protocol, which includes structural and functional imaging as well as amyloid and tau PET. We also quantify gait, and have genetic data and biosamples available for collaborative analyses.

JENNIFER J. MANLY, PHD
Professor of Neuropsychology

Education is a long-established predictor of health, but most studies use years of educational attainment or highest credential without considering school quality, which varies across race/ethnicity, geographic region, and over time. This presentation will show data from non-Hispanic White and Black participants in the REGARDS cohort who were born in the United States between 1908 and 1962, who reported place of residence at age 6; and responded to a Childhood SES mail questionnaire (n=10,792). We linked individuals to historical county and state level administrative data for schools. Longer-term length, higher attendance ratio, and lower student-teacher ratio were related to better self-reported grade school quality, literacy, school resources, and higher educational attainment across race, but these relationships were generally stronger among Blacks. In a larger sample (n = 23,687) a summary measure of school quality predicted lower prevalence of stroke and cognitive impairment, especially among Whites. This study validates a race- and place-specific summary measure of educational policy and demonstrates that later life brain health of both White and Black adults reflects the influence of childhood educational experiences.

NEIL A. SHNEIDER, MD, PHD
Associate Professor of Neurology

Mutations in the gene FUsed in Sarcoma (FUS) are associated with the most aggressive, juvenile-onset forms of amyotrophic lateral sclerosis (ALS). In a series of mouse genetic experiments, we have explored the mechanism(s) of FUS-dependent motor neuron degeneration in ALS. Using insights from these pre-clinical studies, we have initiated a first-in-human trial to treat individual FUS-ALS patients with an experimental, anti-sense oligonucleotide.

CHRISTIANE REITZ, MD, PHD
Associate Professor of Neurology and Epidemiology

In the largest genome-wide association study on Alzheimer disease (AD) in African-Americans we previously implicated ABCA7, an intergenic locus at 5q35, and confirmed TREM2. Increasing the sample size by 37% (2,845 cases, 5,271 controls) and employing the African Genome Resource (AGR) panel we identified three novel common loci near the intracellular glycoprotein trafficking gene EDEM1, the immune response gene ALCAM and GPC6, a gene critical for recruitment of glutamatergic receptors to the neuronal membrane. In addition, we identified rare loci including an intergenic locus near IGF1R at 15q26, API5 at 11p12, and RBFOX1 at 16p13. Gene expression data from brain tissue demonstrate association of ALCAM, GPC6, IGF1R and RBFOX1 with brain beta amyloid load. Of 25 known non-Hispanic white loci, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2 and WWOX were implicated at a nominal significance level or stronger. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying AD in African-Americans overlap with those observed in non-Hispanic whites. While the major pathways involved in AD etiology in African-Americans are similar to those in non-Hispanic whites, the disease associated loci within these pathways differ.

MEGAN BARKER, PHD
Postdoctoral Research Scientist, Cosentino Lab

Language and communication are fundamental to the human experience. Language deficits are observed in almost all neurodegenerative diseases, but tend to be overlooked when they are not one of the presenting symptoms or do not constitute a formal or primary impairment. Using examples of two frontotemporal lobar degeneration (FTLD) case series – patients with progressive supranuclear palsy and tau mutation carriers destined to develop behavioral variant FTD – I will describe how investigating the details, patterns and errors on key neuropsychological tests can help characterize the nature of subtle language problems and provide us with an understanding of the cognitive processes underlying language dysfunction. These findings have implications for accurate diagnosis and phenotyping of degenerative diseases, as well as for clinical strategies and interventions.

LAURA BETH MCINTIRE, PHD
Assistant Professor of Pathology and Cell Biology

Lipidomic data from autopsy brain, human plasma and animal models highlights severe lipid dyshomeostasis in Alzheimer’s disease (AD). The importance of lipid metabolism in AD is supported by GWAS studies which have identified multiple lipid modifying enzymes and interacting proteins. Further, mouse genetic studies have shown benefit of genetic disruption of synaptojanin1 (Synj1), phospholipase A2 (PLA2), phospholipase D2 (PLD2). We showed that haploinsufficiency of synaptojanin1 (Synj1), a phosphoinositide phosphatase, and concurrent maintenance of phosphoinositide levels, ameliorated behavioral deficits in a mouse model of AD in spite of pathological amyloid accumulation. Similarly, disruption of phospholipid modifying enzymes PLD2 and PLA2 resulted in rescue of behavioral deficits despite the pathological accumulation of amyloid. It is likely then that specific pathways in lipid metabolism underlie AD disease mechanisms leading to behavioral impairment. Specifically, the loss of polyunsaturated fatty acids among multiple phospholipid classes is common in AD affected human brain and mouse models. Our lipidomic studies show that lipid species are dramatically altered in mouse brain in a regionally specific manner determined by imaging mass spectrometry. Synthesis of these findings and the fact that disruption of phospholipid modifying enzymes Synj1, PLA2 and PLD2 rescue behavioral deficits in spite of pathological accumulation of amyloid, implicate acyl chain remodeling as a candidate therapeutic target in AD.

LUANA FIORITI, PHD
Adjunct Associate Research Scientist in the Mortimer B. Zuckerman Mind Brain Behavior Institute

Post-translational modifications can modulate aberrant aggregation of proteins. For instance, Tau is hyperphosphorylated when aggregated, but it can also be modified by ubiquitin, SUMO1 and by SUMO2/3. Interestingly SUMO attachment helps protein to remain soluble. Along this line, we discovered that the prion-like protein CPEB3 is SUMOylated by SUMO2 to prevent its aggregation, while SUMO1 does not affect it. A similar role for SUMO inhibition of aggregation has been described for α-synuclein, implicated in Parkinson’s disease. Thus, we tested the role of different SUMOs in Tau-related disorders. We studied how SUMO1 and SUMO2 modulate the toxicity, aggregation and prion-like spreading of Tau in vitro and in vivo. We found that co-expression of SUMO2 but not SUMO1 decreases Tau-induced cell death. Similarly SUMO2 but not SUMO1 decreases the aggregation and release of both wild type and mutant Tau. Our findings on SUMO2 may open up new avenues of therapeutic interventions for Tauopathies.

HILARY GROSSO JASUTKAR, MD, PHD
Postdoctoral Research Fellow, Marder Lab

Autophagy is a lysosome mediated degradation pathway that can degrade a wide range of cargoes from individual proteins to intact organelles. Over the past few decades, a large amount of data has emerged implicating autophagy across a wide array of adult onset neurodegenerative diseases. Specifically, disease-associated mutations have been found in genes coding for proteins important for autophagy, pathogenic proteins of various neurodegenerative diseases have been identified as targets of autophagy, and there is evidence for disrupted autophagy in post-mortem tissue of patients with neurodegenerative conditions. Nonetheless, it is unclear if this pathway is a bystander in these disorders or if it contributes to pathogenesis, and if so, how. To better understand how macroautophagy is utilized by the brain we’ve undertaken a proteomics approach to identify the cargoes degraded by macroautophagy. In addition to mitochondrial proteins, the category of proteins most represented as cargo were synaptic and axonal proteins. Given the importance of synaptic plasticity in cognition and the evidence that the synapse may be an early site of injury in neurodegenerative processes, we hypothesize that autophagy is critical for maintaining the adult synapse, and that this function mediates the role of autophagy in neurodegenerative conditions of cognition. To test this hypothesis we are evaluating synaptic function in the absence of autophagy in adult mice, analyzing autophagic activity in mouse models of the disease state, and investigating the pathway through which synaptic proteins are targeted to the autophagic vacuole.

CHUNSHENG RUAN, PHD
Postdoctoral Research Scientist, Elyaman Lab

Microglia, the brain-resident immune cells, play a critical role in the immune surveillance of the central nervous system (CNS) in many neurodegenerative diseases including Alzheimer’s disease (AD). However, their exact role and regulation by infiltrating adaptive and innate immune cells are either contradictory or very limited. This is due in part to a lack of microglia-specific tools or animal models to distinguish between infiltrating myeloid cells and CNS-resident microglia. Here, we present a novel reporter mouse model (Tmem119-tdTomato), which expresses a specific microglial surface marker - transmembrane protein 119 (TMEM119) encoded by the Tmem119 gene. In this mouse model, tdTomato is specifically expressed on microglia but not on other CNS-resident cells or -infiltrating immune cells, nor in peripheral blood-circulating immune cells. The tdTomato+ cells are detectable in the CNS of adult and aged mice. Using two-photon live imaging, we show that cortical microglia respond within minutes to laser-induced injury. Furthermore, by taking advantage of a commercially-available reporter mouse model that marks all myeloid cells in GFP based on the CX3CR1 expression, we generated a double reporter mouse model (Cx3cr1-GFP/Tmem119-tdTomato) that can be used to distinguish CNS-resident microglia (GFP+tdTomato+) from infiltrating peripheral myeloid cells (GFP+tdTomato-) by two-photon microscopy, confocal microscopy and flow cytometry. Finally, to study microglial phagocytic activity in living animals, we developed a novel amyloid uptake assay in vivo where Tmem119-tdTomato reporter mice receive intracranial microinjection of FITC-labeled Aβ1-42 peptide followed by time-lapse imaging of Aβ1-42 (green) uptake by microglia (red). This innovative mousemodel is critical to track the live effects of therapeutic small molecules or biologics on the dynamics of microglial uptake function during neurodegeneration. Overall, this mouse model provides a valuable tool to study microglia and their interactions with infiltrating immune cells in AD and other neurodegenerative or neuroinflammatory diseases.

YOON A. KIM
PhD Candidate, Santa Maria Lab

Currently, the molecular basis of Alzheimer’s disease (AD) are unclear. However, several studies suggest that altered microRNA (miRNA) expression and/or function plays an important role in the pathogenesis of AD. MiRNAs are a part of vital regulatory mechanism that prevents the deposition of tau protein, implicating miRNAs as a potential target for the treatment or prevention of AD and other tauopathies. However, mechanisms governing how miRNAs are regulated in the brain are poorly understood.

Methylation is a prevalent posttranscriptional modification found in coding and non-coding RNAs that regulates accuracy of translation initiation, stability and biogenesis or processing. Recently, miRNAs have also been found to be targets of RNA methylation. One of the methyltransferases specifically enriched in the brain is NSUN2. Importantly, deficits in memory and learning have been observed in NSUN2-deficient Drosophila melanogaster model and transgenic mice NSUN2 knockout model, indicating a potential role of NSUN2 in cognitive function. Notably, in humans, mutations in the NSUN2 gene can cause disorders that are associated with intellectual disability.

Here we performed histological and biochemical analyses of post-mortem human brains from AD patients and healthy controls. In order to mimic pathological conditions of AD brain in vitro, we treated primary neuronal cultures with synthetic oligomeric Amyloid beta (Ab) and we analyzed the effect alterations in the levels of NSUN2 have on tau proteostasis using a myriad of immunocytochemical and biochemical approaches. In addition, we chose Drosophila as our in-vivo model system to study NSUN2-microRNA modulation of tau neurotoxicity and behavior.

Our data supports dysregulation of NSUN2 in post-mortem brain tissue from AD patients when compared to healthy controls. In addition, we found that oligomeric Aβ induces both dysregulation of NSUN2 and changes in tau proteostasis in primary neuronal cultures. Furthermore, bioinformatic analysis shows predicted methylation sites in miRNAs that have been implicated in AD. Strikingly, our in-vivo data shows that overexpression of NSUN2 can rescue tau induced toxicity.

We propose that NSUN2 mediates methylation of brain miRNAs promoting alterations in tau proteostasis leading to neurodegeneration and cognitive dysfunction. Discovering the earliest events driving alterations in tau proteostasis will identify possible therapeutic targets to slow and/or halt the progression of the disease.

ALLAN LEVEY, MD, PHD
Professor and Chairman of the Department of Neurology at Emory University, Director of the Emory Alzheimer’s Disease Research Center

There is an unmet need to develop novel therapeutic targets and biomarkers for Alzheimer’s disease (AD) and related disorders. Recognizing the complexity of AD, the Accelerating Medicines Partnership (AMP)-AD consortium of academic research teams, NIA, and industry was created to use systems biology approaches and multi-omics profiling of well characterized postmortem human brains to discover and validate new targets and biomarkers for AD. Dr. Levey will discuss the Emory team’s approach, providing an advanced proteomics platform for the entire consortium, using mass spectrometry to deeply profile the protein network alterations in >2000 postmortem human brains. Highly conserved AD proteomic networks include protein co-expression modules strongly associate with diagnosis, cognition, and neuropathology. Experimental validation of several novel protein targets in these modules confirmed links to neurodegeneration in model systems and in human brain pathology. Integrating the brain protein networks with proteomics studies of biofluids also provides a new strategy to directly translate these targets into actionable biomarkers to monitor these modules and the respective pathophysiologies in living subjects. This approach offers potential to develop new therapeutic targets and biomarkers that serve as robust and reproducible indicators of AD, including the dysregulated processes that occur in brain.

CLARISSA WAITES, PHD
Assistant Professor of Pathology and Cell Biology

Stressful life experiences and chronic stress are risk factors for AD. Consistent with these epidemiological findings, unpredictable stress and elevated levels of glucocorticoids (the major stress hormones) trigger AD pathomechanisms in animal models. These include overproduction of amyloid-beta (A) peptides and Tau accumulation/hyperphosphorylation, leading to downstream synapse loss and memory deficits. Here, I will discuss some of our recent work elucidating the molecular mechanisms of stress/glucocorticoid-induced amyloidogenesis and Tau pathology.

FRANCESCA BARTOLINI, PHD
Assistant Professor of Pathology and Cell Biology

Emerging studies from several groups have indicated that dynamic microtubules (MTs), in addition to modified MTs, play key roles in neuronal function. In addition, synaptic biphasic fluctuations of MT instability/stability and tubulin post-translational modifications (PTMs) are associated with memory formation and are disrupted in aging, indicating a primary role for the regulation of MT dynamics and tubulin PTMs in the maintenance of synaptic plasticity. In support of this model, we found that stabilization of dynamic MTs and induction of tubulin PTMs by the formin mDia1 contribute to oligomeric Aβ1-42 synaptotoxicity in vitro and in vivo, and inhibition of MT dynamics alone is sufficient to promote tau hyperphosphorylation and tau dependent synaptotoxicity (Qu et al., J Cell Biol, 2017). To test whether these MT changes occur at synapses and are directly responsible for synapse loss, we have further developed microscopy assays that measure MT invasions into dendritic spines and MT contacts with single presynaptic boutons of hippocampal neurons in culture. We found that dynamic MT plus ends preferentially grow near presynaptic boutons, and nucleation at boutons is enhanced by neuronal activation or when neurons are challenged with oligomeric Aβ1-42 (Aβ), an activity mediated by tau and formin function. Aβ also acutely affected the fraction of spines invaded by MTs, which appeared to be the most resistant to injury-dependent structural plasticity. Our data underscore the existence of a previously uncharacterized pool of presynaptic dynamic MTs that respond to neurotransmission and excitotoxicity, and reveal a function for spine-invading MTs in conferring resistance to pruning.

RUSSELL NICHOLLS, PHD
Assistant Professor of Pathology and Cell Biology

Multiple lines of evidence strongly support the involvement of the serine/threonine phosphatase, PP2A in the molecular etiology of Alzheimer’s disease and tauopathy. PP2A activity is regulated in part through methylation of its catalytic subunit, and this methylation is controlled by the opposing activities of the methylesterase, PME-1, and the methyltransferase, LCMT-1. To explore the mechanisms that underlie the involvement of PP2A in Alzheimer’s disease and tauopathy, we have genetically manipulated LCMT-1 and PME-1 expression in a series of experiments to examine their effects on cognitive and electrophysiological impairments caused by beta-amyloid and tau. Data from these experiments show that increased LCMT-1 expression or reduced PME-1 expression protects mice from cognitive and electrophysiological impairments caused by exposure to elevated levels of either beta-amyloid or tau, and that increased PME-1 expression or reduced LCMT-1 expression sensitizes mice to these impairments. We also found that PME-1 and LCMT-1 regulate sensitivity to beta-amyloid by acting downstream in a pathway that depends on the phosphorylation state of amyloid precursor protein at threonine residue 668. Together these results shed light on the mechanisms by which PP2A participates in Alzheimer’s disease-related cognitive impairments, and suggest possible avenues for therapeutic intervention.

YASIR H. QURESHI, MD
Associate Research Scientist, Small Lab

Retromer is the ‘master conductor’ of endosomal trafficking, and it has been implicated in the endosomal trafficking dysfunction observed in Alzheimer’s disease. Retromer is deficient in Alzheimer’s vulnerable brain regions, and retromer depletion in model systems phenocopies key disease characteristics. It has remained unknown whether retromer repletion can rescue AD-associated endosomal trafficking dysfunction. Here we address this question using mouse models and viral vector technology. We show that retromer repletion rescues neuronal phenotypes observed in AD. Unexpectedly, we also find that retromer repletion rescues a glial phenotype. These findings have mechanistic and therapeutic implications.