Research Projects

Alzheimer’s Disease (AD) is the most common cause of dementia globally but the precise cause of this condition is unknown. Tauopathy is a hallmark pathology for AD. The severity of this pathology is classified on the basis of extent of cortical spread of Tau pathology. The reason for this spatial pattern of Tau spread is not known and is an important question in the field of neurodegeneration research. Several groups have shown that Tau transfer happens trans-synaptically. Astrocytes are glial cells that help to maintain structure and physiological homeostasis of synapse. Normal astrocytes attain a distinct structural and functional state in neurodegenerative and neuroinflammatory environment - this is called the ‘Reactive state’ of astrocyte. What role do reactive astrocytes play in trans-synaptic tau transfer in AD ? The role of reactive astrocytes in transsynaptic Tau transfer has not been explored by any group yet. My hypothesis is - Reactive astrocytes are essential for the trans-synaptic Tau transfer in dementia and interfering in this mechanism could provide a level of neuroprotection in Alzheimer’s disease To test this hypothesis following objectives are proposed to be investigated by methods explained later in technical document. (1) What is the role of reactive astrocytes in trans-synaptic Tau spread in a co- culture system? This will be carried out by using a co-culture system of tau treated neurons and LPS treated astrocytes under varying conditions as described in technical documents. The read out will be expression level of synaptic proteins and autophagy markers using imaging and immunoblot approaches (2) Is there an increase or decrease in abnormal tau assimilation during reactive astrogliosis? This will be investigated using an in vitro system of primary astrocytes treated with abnormal tau and LPS followed by immunochemical investigated (3) Does oligomeric state of abnormal tau influence the tau internalization and release in reactive astrocytes? Characterized abnormal tau oligomers will be incubated with LPS treated astrocytes and immunocytochemistry against tau will be used for determining the internalization kinetics. Significance- : Neuroinflammation is common in Tauopathies. However, the role of reactive astrocyte in Tauopathies and particularly in the spread of Tau pathology at synapse has not been studied. This is the first study to specifically look at the role of reactive astrocytes in trans-synaptic transfer of abnormal Tau. This will also help to clarify the toxic or protective role of astrocytosis in neurodegeneration in broad spectrum of diseases.