Laboratory of Molecular Psychiatry in Aging
Billions of dollars have been spent to develop new drugs to treat Alzheimer’s disease (AD). However, all the phase III clinical trials for AD thus far have failed. We aim to research new drug targets for AD. Our research team has been using the combination of both clinical and preclinical approaches to pursue drug discovery in AD research.
Our study has an emphasis on identifying modifiable risk factors and providing information on effective prevention and intervention for cognitive decline and the development of AD through innovative research by using both human samples and mouse models. Through wide collaborations at Boston University, and nationally and internationally, our research team has been pursuing the following research areas:
- Peripheral chronic inflammation, brain endothelial dysfunction and Alzheimer’s disease
Elderly often suffer from peripheral chronic inflammatory diseases. We hypothesize that certain peripheral inflammatory factors increase AD risk in certain AD genetic risk carriers. Our team has been identifying and studying the communication between peripheral biomarkers and brain abnormalities in aging and the prodromal stage of AD. We are targeting peripheral inflammatory biomarkers that could lead to an early diagnosis of AD, especially those biomarkers which are associated with AD risk in the longitudinal studies. We are also using brain tissues and neuro- imaging, such as magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS), to study these biomarkers and brain composition. While it is widely shown that possessing the ApoE4 gene is the major genetic risk factor of AD, not all ApoE4 carriers develop AD. For the first time, our team has shown that ApoE4 linked with chronic inflammation dramatically increases the risk for AD (JAMA Network Open 2018). Recently we have identified that elevated plasma CRP levels are associated AD biomarkers in cerebral spinal fluid (CSF) only in ApoE4 carriers (Neurology 2021 in press). We are using mouse models to investigate the mechanism on CRP and ApoE4 for AD pathogenesis and have identified that CD31 on brain endothelia binds to monomeric CRP and causes cerebrovascular damage in ApoE4 carriers (Aging Cell 2021 in press).
- Gut-brain axis hormones and neurodegenerative diseases
Amylin is an important gut-brain hormone in the body. Amylin and A share several features: they have similar β-sheet secondary structures, bind to the same amylin receptor, and are both degraded by or bound to insulin degrading enzyme (IDE). Using human fasting plasma samples, we found that concentrations of Aβ1-42 (P < 0.0001) and Aβ1-40 (P < 0.0001) increased with each quartile increase of amylin, but not insulin, after adjusting for age, gender, ethnicity, ApoE4, BMI, diabetes, stroke, kidney function and lipid profile. After reviewing the literature, I found that a big difference between amylin and insulin is that amylin readily crosses the blood brain barrier (BBB), but insulin hardly does so. This significant finding was published in Plos One in 2014, and led our team to study peripheral amylin’s activity on the amyloid pathology of AD in the brain. Using APP transgenic mice, we surprisingly found that chronic intraperitoneal (i.p.) injection of AD animals with both amylin and its analog, pramlintide, reduced the amyloid burden and also lowered the concentrations of Aβ. These treatments significantly improved learning and memory in these mice. These findings led to a publication on Molecular Psychiatry in 2014. Further, we found that increasing quartiles of plasma amylin were positively associated with the test scores of memory, visuospacial and executive function, but not with those of language and attention, as these impairments are associated with preclinical symptoms of AD. We think that both the mouse and human studies conducted by our team suggest that amylin, natural or synthetic, are likely to reduce the AD pathology in the brain and provide a new avenue of treatment for the disease. Currently, our research team is conducting a proof of concept study with a clinical amylin analog, pramlintide, for amnestic MCI and AD patients.
- Loneliness, late life depression and Alzheimer’s disease
Both AD and depression have become increasingly more prevalent in the homebound elderly, leading to higher rates of morbidity, nursing home placement and mortality than those found in the general elderly population. We have identified that low plasma Aβ42, the marker of AD, in depression is real and not caused by antidepressants used by the subjects; this finding was published in Biological Psychiatry. We further found that depression with low Aβ42 combined with high Aβ40 in plasma is associated with poor memory. Based on our study and others, we hypothesize the existence of a potential depression subtype associated with Aβ peptides in plasma, which we have termed “amyloid-associated depression.” This finding and our hypothesis were published in the Archive of General Psychiatry (JAMA Psychiatry now) 2008 and enabled me to receive RO1 funding from the National Institute on Aging. We plan to use neuroimaging and genetic tools to find the mechanism between depression and AD. Recently we have found that the relationship between persistent loneliness in the absence of depression in midlife increases the risk of AD in late life by using Framingham Heart Study (FHS) (Alzheimer’s disease & Dementia 2021 in press).
This study demonstrated a novel pathological mechanism, the competition of ApoE and mCRP to CD31binding, for cerebrovascular neuroinflammation resulting in an early stage of AD pathogenesis in the brain. During the chronic stage of peripheral inflammation, pentameric CRP (pCRP) proteins disassociate into mCRP. mCRP binds to CD31 on blood-facing endothelia to increase CD31 phosphorylation (pCD31), cause damage to the cerebrovasculature and induce extravasation of T lymphocytes into the brain, leading to AD pathogenesis (ApoE4>ApoE3>ApoE2). This process is antagonized by ApoE-CD31 binding (ApoE2>ApoE3>ApoE4) to block mCRP-CD31 binding and differentially regulate pathways (mitochondrial function, epigenetics and vasculogenesis) to intervene in the neurodegenerative process of AD. The research work will be published in Aging Cell 2021 in press.
The Qiu lab utilizes a homebound elderly population in the Boston area. The homebound elderly suffer from a multitude of medical and psychiatric illnesses, including type 2 diabetes, late life depression, and AD (Qiu et al. 2010). Diseases in the elderly often co-exist, one disease may have manifestations in multiple organs, or one disease may lead to the development of another disease. Thus, the homebound elderly population is unique in studying the interaction between diseases in peripheral organs and the brain because of a high percentage of co-existing diseases. With respect to disease research, when following this established cohort population, it is important to identify the biomarkers, modifiable and nonmodifiable factors, and to understand how mutations of the genes interact with the environment to cause diseases in the elderly.
The members of Dr. Qiu’s team share the same goal of working on pathological questions related to research in geriatric psychiatry. We also believe in making our lab a collegial, stimulating, and fun place to work.
Post doctoral fellow
Post doctoral fellow
Senior scientist and statistician
Bioinformatics data scientist
Post doctoral fellow
Post doctoral fellow
Post doctoral fellow
- Qiu WQ, deBruin D, Brownstein BH, Pearse R, Ravetch JV. Organization of the human and mouse low-affinity Fc gamma R genes: duplication and recombination. Science 1990; 248: 723-735.
- Feinman R, Qiu WQ, Pearse RN, Nikolajczyk BS, Sen R, Sheffery M, Ravetch. PU.1 and an HLH family member contribute to the myeloid-specific transcribption of the Fc gamma RIIA promotor. EMBO J. 1994; 3852-60.
- Qiu WQ, Ferreira A, Miller C, Koo EH, Selkoe DJ. Cell-surface beta-amyloid precursor protein stimulates hippocampal neuronal adhesion and neurite outgrowth in an isoform- dependent manner. J Neurosci. 1995; 15: 2157-67.
- Qiu WQ, Walsh D, Ye Z, Vekrellis K, Zhang J, Podlisny M, Rosner M, Safavi A, Hersh LB, Selkoe DJ. Insulin degradation enzyme released from microglial cells degrades extracellular amyloid-beta peptide and stimulates its oligomerization. J Biol Chem. 1998; 273(49): 32730- 32738.
- Vekrellis K, Ye Z, Qiu WQ, Walsh D, Harley D, Chesneau V, Rosner MR, Selkoe DJ. Neurons regulate extracellular levels of amylid beta-protein via proteolysis by insulin- degrading enzyme. J Neurosci 2000; 20(5): 1657-65.
- Qiu WQ and Folstein MF. Insulin, insulin-degrading enzyme and amyloid-b peptide in Alzheimer’s disease: review and hypothesis. Neurobiology of Aging 2006; 27: 190-198
- Qiu WQ, Price LL, Hibber P, Beull J, Collins L, Leins D, Mwamburi DM, Rosenberg, I, Smaldone BA, Scott TM, Siegel RD, Summergrad P, Sun X, Wagner C, Wang L, Yee J, Tucker K and Folstein M. Executive Dysfunction in Homebound Elderly with Diabetes J Ameri Geria Soci 2006; 54: 456-501.
- Sun, X, Mwamburi, Bungay, K, Prasad, J, Yee, J, Lin, Y, Liu, TC, Summergrad, P, Folstein, M and Qiu, WQ: Depression, Antidepressants and Plasma Ab Peptides in those Elderly who do not have Cardiovascular Disease. Biological Psychiatry 2007; 62: 1413-7
- Sun, X; Steffens, D.C; Folstein, M; Summergrad, P; Yee, J; Rosenberg, I; Au, R; Mwamburi, D.M and Qiu, WQ: Amyloid-associated depression: A prodromal depression of Alzheimer’s disease? Arch Gen Psych 2008, 65: 542-50
- Sun, X; Chiu, C.C; Liebson, E; Crivello, N. A; Wang, L; Folstein, M; Rosenberg, I; Mwamburi; Peter, I and Qiu, WQ: Depression and plasma Amyloid β peptides in the elderly with and without apolipoprotein E4 allele. Alzheimer’s Disease & Associated Disorder 2009, 23: 238-44
- Sun, X; Bhadelia RA; Liebson, E; Bergethon P; Folstein, M; Zhu, JJ; Mwamburi; Patz, S and Qiu, WQ: The Relationship between Plasma Amyloid-β Peptides and the Medial Temporal Lobe in the Homebound Elderly. Int J. Ger Psych 2010, in press
- Qiu WQ and Zhu H: Amylin and its analogs: a friend or foe for the treatment of Alzheimer’s disease? Front Aging Neurosci. 2014 Jul 29; 6:186
- Zhu H; Wang X; Wallack M; Li H; Carreras I; Dedeoglu A; Hur J; Zheng H; Li H; Fine R; Sun X; Mwamburi M; Kowall N; Stern R; and Qiu WQ: Intraperitoneal Injection of the Pancreatic Peptide Amylin Potently Reduces Behavioral Impairment and Brain Amyloid Pathology In Murine Models of Alzheimer’s Disease. Molecular Psychiatry 2015 Feb; 20(2): 252-62
- Li H; Zhu H; Scott T; Wallack M; Mwamburi M; Abdul-Hay SO; Lessring M and Qiu WQ: Age and its association with low insulin and high amyloid-β peptides in blood. J. Alzheimer’s disease, 2015; 49(1): 129-37
- Wang, E; Zhu, H; Wang, X; Gower, A; Wallack, M; Blusztajn, JK; Kowall, N and Qiu, WQ: Amylin treatment reduces neuroinflammation and ameliorates abnormal patterns of gene expression in the cerebral cortex of Alzheimer’s disease mouse model. J. Alzheimer’s disease, 2017; 56: 47-61
- Zhu, H; Stern, RA; Tao, Q; Bourlas, A; Essis, MD; Chivukula, M; Rosenzweig, J; Steenkamp, D; Xia, W; Mercier, GA; Tripodis, Y; Farlow, M; Kowall, N and Qiu, WQ: An amylin analog used as a challenge test for Alzheimer’s disease. Alzheimer’s Disease & Dementia: Translational Research & Clinical Interventions, 2017 Jan; 3:33-43
- Zhu H; Xue X; Wallack M; Na H; Hooker JM; Kowall N; Tao Q; Stein TD; Wolozin B; and Qiu WQ: Amylin receptor ligands reduce the pathological cascade of Alzheimer’s disease. Neuropharmacology 2017 Mar 28. Pli:S0028-3908
- Qiu WQ: Amylin and its G-protein-coupled receptor: a probable pathological processand drug target for Alzheimer’s disease, Neuroscience 2017 Jul 25;356:44-51
- Tao Q; Zhu H; Chen X; Stern RA; Kowall N; Au R; Blusztajn JK and Qiu WQ: Pramlintide: the effects of a single drug injection on blood phosphatidylcholine profile for Alzheimer’s disease. J. Alzheimer’s Disease 2018; 62(2):597-609 PMC 5956916
- Tao Q, Ang T, DeCarli C, Auerbach SH, Devine S, Stein TD, Zhang X, Massaro J, Au A and Qiu WQ: Association of chronic low-grade inflammation with risk of Alzheimer disease in ApoE4 carriers. JAMA Network Open 2018; 70(4): 1025-1040, PMC 6324596
- Gan Q, Yao H, Na H, Balance H, Tao Q, Leung L, Tian H, Zhu H, Wolozin B and Qiu WQ: Amylin’s effects against Aβ induced tauopathy and synapse loss in primary neurons. Journal of Alzheimer’s Disease 2019; 70(4): 1025-1040. PMC: 6833957
- Zhu H, Tao Q, Ang T, Massaro J, Gan Q, Salim S, Zhu R, Kolachalama VB, Zhang X, Devine S, Auerbach SH, DeCarli C, Au A and Qiu WQ: Association of plasma amylin concentration with Alzheimer’s disease and brain structure in older adults. JAMA Network Open 2019; 2(8): e199826. PMC: 6707010
- Na H, Gan Q, Mcparland L, Yang JB, Yao H, Tian H, Zhang Z and Qiu WQ: Characterization of the effects of calcitonin gene-related peptide receptor antagonist for Alzheimer’s disease. Neuropharmacology 2020; 168:108017.
- Sugarman MA, Zetterberg H, Blennow K, Tripodis Y, McKee AC, Stein TD, Martin B, Palmisana JN, Steinber EG, Simkin I, Budson AE, Killiany R, O’Connor MK, Au R, Qiu WQ, Goldstein LE, Kowall NW, Mez J, Stern RA, Alosco ML. A longitudinal examination of plasma neurofilament light and total tau for the clinical detection and monitoring of Alzheimer’s disease. Neurobiology of Aging 2020. 94: 60-70
- Akhter-Khan SC*, Tao Q*, Ang TFA, Itchapurapu IS, Alosco ML, Mez J, Piers RJ, Steffens DC, Au R and Qiu WQ. Associations of loneliness with risk of Alzheimer’s disease dementia in the Framingham Heart Study. Alzheimer’s & Dementia 2021 Mar 24. doi: 10.1002/alz.12327
- Na H, Tian H, Zhang Z, Li Q, Yang JB, Mcparland L, Gan Q and Qiu WQ: Oral amylin treatment reduces the pathological cascade of Alzheimer’s disease in a mouse model. American J. Alzheimer’s Disease 2021 in press
- Tao Q, Ang T, Akhter-khan S, Itchapurapu IS, Killiany R, Zhang X, Budson AE, Turk KW, Goldstein L, Mez J, Alosco ML and Qiu WQ: Impact of C-Reactive Protein on Cognition and Alzheimer Disease Biomarkers in homozygous Apolipoprotein E ɛ4 Carriers. Neurology 2021 in press
- Zhang Z, Na H, Gan Q, Tao Q, Alekseyev Y, Hu J, Yan J, Yang JB, Tian JB, Zhu S, li Q, Rajab IM, Blusztajn JK, Wolozin B, Emili A, Zhang X, Stein T, Potempa LA and Qiu WQ: Competition between distinct ApoE alleles and mCRP for the endothelial receptor CD31 differentially regulates neurovascular inflammation and Alzheimer’s disease pathology. Aging Cell 2021.
Wendy Qiu, M.D., Ph.D.
72 East Concord Street, R-623B
Boston, MA 02118