Pathophysiology

Despite only accounting for a minority of neurodegenerative disease cases, select familial mutations have served as archetypes of neurodegeneration to those probing molecular underpinnings in model systems. While benefiting from the predictability and intensity such mutations offer to those using model systems, the field has tended to over-generalize findings – presupposing that pathophysiology due to familial mutations is indicative of pathophysiology in the more common, sporadic neurodegeneration cases.

Aiming to identify broadly relevant effectors of neurodegenerative diseases, I am, instead, turning to the wealth of epidemiologic literature to create experimental models capable of probing pathophysiology. While familial mutations account for fewer than 1% of Alzheimer's disease cases, well-established population-attributable factors are thought to contribute up to 40% of dementia risk at a population level. I study these population-attributable factors in human postmortem series and in animal model systems to identify new therapeutic targets for neurodegeneration.

NEURODEGENERATIVE PATHOGENESIS AND THE LOCUS COERULEUS

The locus coeruleus is a deeply conserved brainstem nucleus responsible for the vast amount of norepinepherine production in the brain. Morphological constraints have limited isometric scaling between the locus coeruleus and total brain size, possibly subjecting it to a great deal of oxidative and metabolic stress in large-brained animals such as humans. Several neurodegenerative diseases, including Alzheimer’s, feature early neurodegeneration in the locus coeruleus. I am interested in the factors that contribute to the early vulnerability of the locus coeruleus in neurodegenerative diseases, as well as the clinical ramifications of locus coeruleus vulnerability for neurodegenerative diseases and aging.

STRESS AND ISOLATION AS A RISK FACTOR FOR NEURODEGENERATIVE DISEASE

There are complex, poorly elucidated interactions between an individual’s social environment and brain structure and function. Veterans with post-traumatic stress disorder (PTSD) have a nearly two-fold higher risk for developing dementia than those without, suggesting that structural and functional neurological changes occurring due to stress may contribute to neurodegeneration. Furthermore, the risk of developing AD-type dementia has been shown to be markedly increased in socially isolated geriatric populations, suggesting that social enrichment plays a significant role in biological resistance to neurodegeneration and/or reserve against cognitive changes. I am interested in the biological substrate on which an individual’s life history and social environment contributes to neurodegenerative pathophysiology. Using animal models, I’m able to tightly control social stressors to elucidate molecular changes in conserved regions like the locus coeruleus. Deep molecular phenotyping of human postmortem tissue enables verification of the clinical relevance of the molecular changes detected in animal models and guides further work to determine which pathways are necessary and sufficient to moderate the associations between social stress and neurodegeneration.  

Featured publications

Ehrenberg AJ, Suemoto CK, Resende EDPF, Petersen C, Leite REP, Rodriguez RD, Ferretti-Rebustini REL, You M, Oh J, Nitrini R, Pasqualucci CA, Jacob-Filho W, Kramer J, Gatchel J, Grinberg LT. Neuropathologic correlates of psychiatric symptoms in Alzheimer’s disease. Journal of Alzheimer’s Disease. 66(1): 115-126. 2018. PMID: 30223398. PubMed

Eser RA, Ehrenberg AJ, Petersen C, Dunlop S, Mejia MB, Suemoto CK, Walsh CM, Rajana H, Oh J, Theofilas P, Seeley WW, Miller BL, Neylan TC, Heinsen H, Grinberg LT. Selective Vulnerability of Brainstem Nuclei in Distinct Tauopathies: A Postmortem Study. Journal of Neuropathology and Experimental Neurology. 77(2): 149-161. 2018. PMID: 29304218. PubMed

Ehrenberg AJ, Nguy AK, Theofilas P, Dunlop S, Suemoto CK, Alho AT, Leite RP, Rodriguez RD, Mejia MB, Rüb U, Farfel JM, Ferretti-Rebustini REL, Nascimento CF, Nitrini R, Pasquallucci CA, Jacob-Filho W, Miller B, Seeley WW, Heinsen H, Grinberg LT. Quantifying the accretion of hyperphosphorylated tau in the locus coeruleus and dorsal raphe nucleus: the pathological building blocks of early Alzheimer's Disease. Neuropathology and Applied Neurobiology. 43(5): 393-408. 2017. PMID: 28117917. PubMed

Theofilas P, Ehrenberg AJ, Dunlop S, Di Lorenzo Alho AT, Nguy A, Leite REP, Rodriguez RD, Mejia MB, Suemoto CK, Ferretti-Rebustini REL, Polichiso L, Nascimento CF, Seeley WW, Nitrini R, Pasqualucci CA, Filho WJ, Rueb U, Neuhaus J, Heinsen H, Grinberg LT. Locus coeruleus volume and cell population changes during Alzheimer's disease progression: A stereological study in human postmortem brains with potential implication for early-stage biomarker discovery. Alzheimer's & Dementia: The Journal of the Alzheimer's Association. 13(3): 236-246. 2017. PMID: 27513978. PubMed