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Abstract
Alzheimer’s disease (AD) and Lewy body diseases (LBD) are the two most common age-related neurodegenerative diseases characterized by neuronal loss and abnormal protein aggregations (Aβ and phosphorylated tau in AD, and α-synuclein in LBD). Ageing is the single most common risk factor for both AD and LBD, and neuronal senescence may therefore be a potential underlying factor for these diseases. Whether neuronal senescence increases with age or age-related neurodegenerative diseases, and whether it is related to the cell loss and protein deposition observed remains to be determined. Following institutional approvals, formalin fixed brain tissue samples were acquired from the New South Wales Brain Banks for 35 elderly controls, 10 AD, 17 LBD and 6 multiple system atrophy (MSA) cases. Depending on the study, dissociated nuclei from the hippocampal CA1 region, the anterior cingulate cortex, the substantia nigra and/or the pontine base were assessed using flow cytometry for cell number (validated using optical methods) and average DNA content, and immunohistochemistry for the severity of protein deposition and the expression of the cell senescence marker, nuclear P16INK4a. Initial assessment of aneuploidy revealed no significant increase during normal brain ageing, no increase in the α-synucleinopathy MSA, but significantly more hyperploid neurons in AD and LBD. The increase in hyperploid neurons occurred prior to significant neuronal loss in cortical regions, relating most to AD type protein depositions, but also independently to substantia nigra cell loss. These relationships were confirmed by assessing the nuclear expression of cell cycle repressor P16INK4a which was decreased in both tangle-bearing neurons and tangle-free neurons, and negatively associated with the increase in aneuploidy. Importantly, the reduction in nuclear P16INK4a occurred in controls with high tau burden, showing that the loss of nuclear P16INK4a occurs prior to the induction of aneuploidy. Overall the data suggest that reduced nuclear expression of P16INK4a predisposes neurons to aneuploidy and neurodegeneration. Further identification of the mechanisms involved are required, and the early events precipitating a reduction in nuclear P16INK4a need to be determined.