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 g enerally thought to arise from gradual extracellular amyloid deposition. We have investigated the possibility of a link between these two apparently c onflicting observations. Methods and results: Immunohistochemistry and digital image analysis was us ed to examine the detailed localization of beta -amyloid(42) (A beta 42), a major component of amyloid plaques, in the entorhinal cortex and hippocamp us of AD brains, A beta 42 first selectively accumulates in the perikaryon of pyramidal cells as discrete, granules that appear to be cathepsin D-posi tive, suggesting that they may represent lysosomes or lysosome-derived stru ctures, AD brain regions abundantly populated with pyramidal neurones exhib iting excessive A beta 42 accumulations also contained evidence of neuronal lysis, Lysis of these A beta 42-burdened neurones apparently resulted in a local, radial dispersion of their cytoplasmic contents, including A beta 4 2 and lysosomal enzymes, into the surrounding extracellular space. A nuclea r remnant was found at the dense core of many amyloid plaques, strengthenin g the idea that each amyloid plaque represents the end product of a single neuronal cell lysis, The inverse relationship between the amyloid plaque de nsity and pyramidal cell density in the AD brain regions also supports this possibility, as does the close correlation between plaque size and the siz e of local pyramidal cells. Conclusions: Our findings suggest that excessive intracellular accumulation of A beta 42-positive material in pyramidal cells can result in cell lysis , and that cell lysis is an important source of amyloid plaques and neurona l loss in AD brains.