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:

  1. 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).

  1. 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.

  1. 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).

ApoE2 vs. ApoE4 carriers in the brain
A model illustrating the differential responses of ApoE2 vs. ApoE4 carriers to peripheral proinflammatory factors like monomeric C-reactive protein (mCRP) and the differential regulation of mCRP-induced cerebrovascular neuroinflammation leading to AD pathogenesis in the brain.

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.