The hallmarks of Alzheimer's disease (AD) are amyloid-β (Aβ) and hyperphosphorylated tau (HP-T). The amyloid cascade hypothesis postulates that Aβ accumulation leads to HP-T expression. It has been recently suggested that Aβ plays a role in the development of α- synuclein (α-syn) pathology, the main constituent of Lewy bodies, which characterise Lewy body disease (LBD). Currently, the putative interactions between Aβ and HP-T/ α-syn are largely unknown. Recent data has suggested a subspecies of Aβ, termed ‘pyroglutamylated Aβ’ (pAβ), may play a crucial role in pathology. pAβ is more abundant in AD and is cytotoxic in the presence of HP-T. pAβ expression also correlates with the presence of HP-T and clinical dementia.
To further investigate the role of pAβ in AD and LBD we are currently using brain tissue from the Newcastle Brain Tissue Resource to quantitatively assess pAβ, HP-T and α-syn, and will compare the results with clinical findings. Using immunohistochemical and biochemical techniques we aim to correlate pAβ with neurofibrillary tangle development, and assess its potential role in synaptic injury and inflammatory response. In addition, we will compare pAβ expression in cerebrospinal fluid (CSF) with parenchymal deposits in the brain. The results will clarify if pAβ plays a crucial role in the pathogenesis of both AD and LBD. If so, pAβ may represent a potential biomarker in CSF and imaging diagnostics, and therapeutic target.
This project is led by Dr Lauren Walker and is funded by the Alzheimer's society.
Publication
Mandler M, Walker L, Santic R, Hanson P, Upadhaya AR, Colloby SJ, Morris CM, Thal DR, Thomas AJ, Schneeberger A, Attems J (2014) Pyroglutamylated amyloid-β is associated with hyperphosphorylated tau and severity of Alzheimer's disease. Acta Neuropathol 128:67-79.