Mitochondrial calcium deregulation and memory loss in Alzheimer's disease

Heng Du, MD, PhD University of Texas at Dallas


Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by gradual cognitive decline currently without effective therapy. Although the detailed molecular mechanisms still remain elusive, defected mitochondrial Calcium modulation has been repeatedly linked with synaptic dysfunction and neuronal death in AD milieus. In the proposed study, we will perform an examination of the role of mitochondrial calcium uniporter (MCU) deregulation in the development of mitochondrial and synaptic pathology in AD. Positive findings will foster our understanding of AD and shed light on the development of novel AD therapeutic avenue targeting MCU.

Project Details

Our overarching goal is to decipher the mechanisms of mitochondrial Ca2+ overload and its impact on cognition in Alzheimer's disease (AD). This is because excess mitochondrial Ca2+ loading underlies synaptic dysfunction and neuronal death in AD milieus, culminating in cognitive impairment. Mitochondrial calcium uniporter (MCU) is the major mitochondrial Ca2+ entry pathway. Experimentally, we will employ biochemical and pathological approaches to establish a link between the deregulation of MCU and mitochondrial dysfunction in AD (aim 1). In view of the importance of mitochondrial fitness for synaptic function, we will determine the influence of MCU deregulation on synaptic plasticity and transmission (aim 2) and cognition (aim 3) in AD-related conditions. This study focuses on an unknown mechanism that underlies mitochondrial dysfunction and synaptic defects, that may contribute to cognitive impairment in AD-related conditions. Positive results will reveal a novel mitochondrial mechanism underlying synaptic injury in AD-related conditions and shed light on the development of new therapeutic avenue for AD treatment. In addition, the proposed study will also provide a novel target to advance research on other types of dementia, for example, Down's syndrome and Lewy body dementia with brain amyloidosis and mitochondrial dysfunction.