The Role of Misdirected Plasticity in Plaque Biogenesis and Alzheimer’s Disease Pathology

Summary

Studies on animal models over the past several years have demonstrated that neurons have the capacity to sprout and form new connections after injury or cell loss. This process may represent the plasticity by which the brain can modify its circuitry and compensate for neuronal or synaptic loss after trauma and in a variety of disease states. Lesions of the entorhinal cortex in the rodent brain and degenerative cell loss in this region in Alzheimer’s disease (AD) are both accompanied by axon sprouting in the dentate gyrus. Animal models have accurately predicted the nature of the sprouting response except for the presence of senile plaques within the area of active sprouting. We have proposed that misdirected sprouting may contribute to plaque biogenesis in this region. The core of senile plaques consists of β/A₄ protein. Synthetic peptides homologous to the β/A₄ protein (β1–28 and β1–42) enhance survival in cultures of hippocampal neurons and the β1–42 fragment increases dendrite number, dendritic branching, and axonal elongation. This suggests that β/A₄ protein may participate in anomalous growth-related events in vivo. The morphological diversity of plaques may reflect different stages of plaque formation in which plasticity processes themselves become misdirected, overcompensated, or generate an enhanced vulnerability in the highly plastic brain areas essential to higher cognitive function.