Small-diffusible aggregates, plaques, tangles, and dynamic equilibria: Untangling Alzheimer's disease

Abstract

INTRODUCTION

Beta-amyloid plaques and hyperphosphorylated tau tangles are the neuropathological hallmarks of Alzheimer's disease; however, their relevance in the pathophysiology is not fully understood. It has been suggested that these larger and insoluble aggregates may not be the most toxic forms of beta-amyloid and tau in Alzheimer's disease, and the disease progression may actually be promoted by the small-diffusible aggregates.

METHODS AND RESULTS

We combine the recent findings from our group and other key research to put forward the hypotheses that the formation of the small-diffusible aggregates of beta-amyloid and tau and their larger insoluble counterparts is not a linear process.

DISCUSSION

While the small-diffusible aggregate formation of beta-amyloid and tau is a passive process, regulated by thermodynamic equilibria, the formation of large-insoluble aggregates is an active process, regulated by microglia and neurons, which to an extent is a protective mechanism against the toxicity of the smaller aggregates.

Highlights

• Plaques and tangles may be made by active processes in Alzheimer's disease.
• The small-soluble aggregates may be the more toxic species in Alzheimer's disease.
• Pathology may be caused by the imbalance of production and clearance of aggregates.
• Plaques and tangle formation may be attempts to restore the homeostatic equilibrium.