Evidence that neurones accumulating amyloid can undergo lysis to form amyloid plaques in Alzheimer's disease

Aims: Amyloid has recently been shown to accumulate intracellularly in the brains of patients with Alzheimer's disease (AD), yet amyloid plaques are generally thought to arise from gradual extracellular amyloid deposition. We have investigated the possibility of a link between these two apparently conflicting observations. Methods and results: Immunohistochemistry and digital image analysis was used to examine the detailed localization of β-amyloid₄₂ (Aβ42), a major component of amyloid plaques, in the entorhinal cortex and hippocampus of AD brains. Aβ42 first selectively accumulates in the perikaryon of pyramidal cells as discrete, granules that appear to be cathepsin D-positive, suggesting that they may represent lysosomes or lysosome-derived structures. AD brain regions abundantly populated with pyramidal neurones exhibiting excessive Aβ42 accumulations also contained evidence of neuronal lysis. Lysis of these Aβ42-burdened neurones apparently resulted in a local, radial dispersion of their cytoplasmic contents, including Aβ42 and lysosomal enzymes, into the surrounding extracellular space. A nuclear remnant was found at the dense core of many amyloid plaques, strengthening the idea that each amyloid plaque represents the end product of a single neuronal cell lysis. The inverse relationship between the amyloid plaque density and pyramidal cell density in the AD brain regions also supports this possibility, as does the close correlation between plaque size and the size of local pyramidal cells. Conclusions: Our findings suggest that excessive intracellular accumulation of Aβ42-positive material in pyramidal cells can result in cell lysis, and that cell lysis is an important source of amyloid plaques and neuronal loss in AD brains.