Alberto Serrano-Pozo, M.D. Ph.D.


Assistant Professor of Neurology
Harvard Medical School
Physician Investigator (Cl)
Neurology, Mass General Research Institute
Assistant In Neurology
Massachusetts General Hospital
PhD University of Seville School of Medicine (Spain) 2013
Research Fellowship in Dementias University Hospital Virgen del Rocío, Seville (Spain) 2008
Neurologist University of Iowa, Iowa city 2017
MD University of Mlaga-Spain 2001
Fellowship in Clinical Dementias Massachusetts General Hospital 2018
Neurologist University Hospital Virgen del Rocío, Seville (Spain) 2006
alzheimer's disease; astrocytes; dementia with lewy bodies; dementias; microglia; neurodegeneration; neurodegenerative diseases; neurofibrillary tangles; neurology; plaque amyloid; tau proteins; tauopathies Our research investigations initially focused on investigating clinic-pathologic correlations within the Alzheimer's disease (AD) continuum from normal aging to end-stage dementia through quantitative neuropathological studies on postmortem brain specimens from the Massachusetts Alzheimer's Disease Research Center (MADRC) Brain Bank, and statistical analyses of the National Alzheimer’s Coordinating Center (NACC) autopsy dataset.

Our analyses of the AD clinico-pathological correlations in the NACC autopsy cohort have revealed that (1) neuritic amyloid plaques, neurofibrillary tangles, moderate and severe cerebral amyloid angiopathy (CAA), severe ischemic small vessel disease, and hippocampal sclerosis all independently correlate with the degree of antemortem cognitive impairment [1]; (2) a subset of patients (»15%) diagnosed with probable mild-to-moderate AD, who would meet criteria for enrollment in anti-amyloid-beta clinical trials, actually have none or only sparse neuritic amyloid plaques [2]; and (3) the extent of amyloid deposition as indicated by Thal amyloid phases is not an independent predictor of antemortem cognition [3]. In addition, we have investigated the associations of APOE genotype with both postmortem AD neuropathological changes and cognitive trajectories during life. We have observed that (1) the allele APOEe4 is associated with more neuritic plaques and CAA, whereas the APOEe2 allele is associated with fewer tangles [4]; (2) neither APOE allele is independently associated with antemortem cognitive performance but each impacts antemortem cognition (e2 is protective and e4 detrimental) through its effects on AD pathology [4]; (3) APOEe4 accelerates cognitive decline and APOEe2 slows it down in subjects who end up having moderate or high AD neuropathological changes [5].

Our stereology-based quantitative neuropathological studies have provided insights about the interactions of reactive glia and AD core pathological features (plaques and tangles) over the course of the disease. Reactive reactive astrocytes and microglia accrue over the course of AD, both paralleling the extent of tangles and diverging from plaque deposition, which remains relatively stable throughout the clinical phase of the disease [6]. This increase in reactive glia occurs in the proximity of both plaques and tangles. However, only the number of reactive (e.g., GFAP+) astrocytes and microglia (e.g., MHC2+), but not their total numbers —reactive plus homeostatic cells– significantly differs between AD and age-matched non-demented individuals, indicating that a phenotypic change but not proliferation underlies glial responses in AD [7]. 

In recent years, it is becoming clear that astrocyte and microglial responses are complex and heterogeneous. We are currently trying to decipher this complexity and heterogeneity by combining biochemical, immunohistochemical, and transcriptomic studies in human postmortem brain specimens and mouse models, as well as manipulating astrocytes from AD mouse models via viral gene transfer. For example, we have characterized the postmortem brain expression of the 18 kDa translocator protein (TSPO), which has been used for almost 20 years as target to develop radioligands for “activated microglia PET imaging”; we found that its overall expression levels are surprisingly similar between AD and age-matched control brains, and that it is expressed not only by microglia but also by astrocytes, endothelial cells, and vascular smooth muscle cells [8]. We have also demonstrated the context-dependent nature of astrocyte reaction by meta-analyzing published astrocyte-specific transcriptomic datasets from mouse models of acute CNS injury and neurodegenerative diseases; indeed, we observed notable differences between both scenarios [9]. Despite this evidence for heterogeneity, neuroinflammation emerged as one of the main pan-neurodegenerative pathways in a meta-analysis of 60 human AD, LBD, and ALS-FTD microarray datasets comprising 2,600 samples, supporting the existence of common glial responses shared across these clinically and pathologically very different neurodegenerative diseases [10]. Ongoing studies are also aiming to elucidate the influence of the APOE genotype on glial phenotypes [11] and the triggers, mechanisms, and consequences of reactive astrogliosis [12].


Selected Publications:

  1. Serrano-Pozo A, Qian J, Monsell SE, Frosch MP, Betensky RA, Hyman BT. Examination of the clinico-pathologic continuum of Alzheimer disease in the autopsy cohort of the National Alzheimer Coordinating Center. J Neuropathol Exp Neurol 2013; 72(12): 1182-1192. [PMCID: PMC3962953]
  2. Serrano-Pozo A, Qian J, Monsell SE, Blacker D, Gómez-Isla T, Betensky RA, Growdon JH, Johnson K, Frosch MP, Sperling RA, Hyman BT. Mild to moderate Alzheimer dementia with insufficient neuropathological changes. Ann Neurol 2014; 75(4): 597-601. [PMCID: PMC4016558]
  3. Serrano-Pozo A, Qian J, Muzikansky A, Monsell SE, Montine TJ, Frosch MP, Betensky RA, Hyman BT. Thal amyloid stages do not significantly impact the correlation between neuropathological change and cognition in the Alzheimer disease continuum.J Neuropathol Exp Neurol 2016; 75(6): 516-26. [PMCID: PMC6250207]
  4. Serrano-Pozo A, Qian J, Monsell SE, Betensky RA, Hyman BT. APOEe2 is associated with milder clinical and pathological Alzheimer’s disease. Ann Neurol 2015; 77(6): 917-929. [PMCID: PMC4447539]
  5. Qian J, Betensky RA, Hyman BT, Serrano-Pozo A. Association of APOE genotype with heterogeneity of cognitive decline rate in Alzheimer’s disease. Neurology 2021 (in press).
  6. Serrano-Pozo A, Mielke ML, Gómez-Isla T, Betensky RA, Growdon JH, Frosch MP, Hyman BT. Reactive glia not only associates with plaques but also parallels tangles in Alzheimer’s disease. Am J Pathol 2011; 179(3): 1373-1384. [PMCID: PMC3157187]
  7. Serrano-Pozo A, Gómez-Isla T, Growdon JH, Frosch MP, Hyman BT. A phenotypic change but not proliferation underlies glial responses in Alzheimer disease. Am J Pathol 2013; 182(6): 2332-2344. [PMCID: PMC3668030]
  8. Gui Y, Marks JD, Das S, Hyman BT, Serrano-Pozo A. Characterization of the 18 kDa translocator protein (TSPO) in post-mortem normal and Alzheimer’s brains. Brain Pathol 2020; 30(1): 151-164. [PMCID:PMC6904423]
  9. Das S*, Li Z*, Noori A, Hyman BT, Serrano-Pozo A. Meta-analysis of mouse transcriptomic studies supports a context-dependent astrocyte reaction in acute CNS injury versus neurodegeneration. J Neuroinflammation 2020; 17(1): 227. [PMCID: PMC7393869] 
  10. Noori A, Mezlini AM, Hyman BT, Serrano-Pozo A*, Das S*. Systematic review and meta-analysis of human transcriptomics reveals neuroinflammation, deficient energy metabolism, and proteostasis failure across neurodegeneration. Neurobiol Dis 2021; 149: 105225. [PMCID: PMC7856076]
  11. Serrano-Pozo A, Das S, Hyman BT. APOE and Alzheimer’s disease: advances in genetics, pathophysiology, and therapeutic approaches. Lancet Neurol 2021; 20(1): 68-80. 
  12. Escartin C*, Galea E*, Lakatos A**, O’Callaghan J**, Petzold G**, Serrano-Pozo A**, Steinhäuser C**, Volterra A**, Carmignoto G**, Agarwal A, Allen N, Araque A, Barbeito L, Barzilai A, Bergles D, Bonvento G, Butt A, Chen W-T, Cohen-Salmon M, Cunningham C, Deneen B, de Strooper B, Diaz-Castro B, Farina C, Freeman M, Gallo V, Goldman J, Goldman S, Gotz M, Gutierrez A, Haydon P, Heiland D, Hol E, Holt M, Iino M, Kastanenka K, Kettenmann H, Khakh B, Koizumi S, Lee CJ, Liddelow S, MacVicar B, Magistretti P, Messing A, Mishra A, Molofsky A, Murai K, Norris C, Okada S, Oliet S, Oliveira J, Panatier A, Parpura V, Pekna M, Pekny M, Pellerin L, Perea G, Perez-Nievas B, Pfrieger F, Poskanzer K, Quintana F, Ransohoff R, Riquelme-Perez M, Robel S, Rose C, Rothstein J, Rouach N, Rowitch D, Semyanov A, Sirko S, Sontheimer H, Swanson R, Vitorica J, Wanner I, Wood L, Wu J, Zheng B, Zimmer E, Zorec R, Sofroniew M*, Verkhratsky A*. Reactive astrocyte nomenclature, definitions, and future directions. Nat Neurosci 2021; 24(3): 312-25.


Amyloid plaques (red) surrounded by GFAP+ reactive astrocytes (cyan), many of them low in EAAT2 (golden), in the temporal cortex of an Alzheimer’s disease patient.
Amyloid plaques (red) surrounded by GFAP+ reactive astrocytes (cyan), many of them with low levels of the glutamate transporter
EAAT2/GLT-1 (golden), in layer V of the temporal cortex of a brain with Alzheimer’s disease.

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