Clusterin contributes to early stage of Alzheimer's disease pathogenesis

While clusterin is reportedly involved in Alzheimer's disease (AD) pathogenesis, how clusterin interacts with amyloid-beta (A beta) to cause A beta neurotoxicity remains unclear in vivo. Using 5xFAD transgenic mice, which develop robust AD pathology and memory deficits when very young, we detected interactions between clusterin and A beta in the mouse brains. The two proteins were concurrently upregulated and bound or colocalized with each other in the same complexes or in amyloid plaques. Neuropathology and cognitive performance were assessed in the progeny of clusterin-null mice crossed with 5xFAD mice, yielding clu(-/-);5xFAD and clu(+/+);5xFAD. We found far less of the various pools of A ss proteins, most strikingly soluble A beta oligomers and amyloid plaques in clu(-/-);5xFAD mice at 5 months of age. At that age, those mice also had higher levels of neuronal and synaptic proteins and better motor coordination, spatial learning and memory than age-matched clu(+/+);5xFAD mice. However, at 10 months of age, these differences disappeared, with A beta and plaque deposition, neuronal and synaptic proteins and impairment of behavioral and cognitive performance similar in both groups. These findings demonstrate that clusterin is necessarily involved in early stages of AD pathogenesis by enhancing toxic A beta pools to cause A beta-directed neurodegeneration and behavioral and cognitive impairments, but not in late stage.