Critical role of intraneuronal Aß in Alzheimer's disease: technical challenges in studying intracellular Aß.

ABSTRACT

AIMS: Multiple lines of evidence have implicated ß-amyloid (Aß) in the pathogenesis of Alzheimer's disease (AD). However, the mechanism(s) whereby Aß is involved in the disease process remains unclear. The dominant hypothesis in AD has been that Aß initiates the disease via toxicity from secreted, extracellular Aß aggregates. More recently, an alternative hypothesis has emerged focusing on a pool of Aß that accumulates early on within AD vulnerable neurons of the brain. Although the topic of intraneuronal Aß has been of major interest in the field, technical difficulties in detecting intraneuronal Aß have also made this topic remarkably controversial. Here we review evidence pointing to the critical role of intraneuronal Aß in AD and provide insights both into challenges faced in detecting intracellular Aß and the prion-like properties of Aß. MAIN METHODS: Immunoprecipitation and Western blot are used for Aß detection. KEY FINDINGS: We highlight that a standard biochemical method can underestimate intraneuronal Aß and that extracellular Aß can up-regulate intracellular Aß. We also show that detergent can remove intraneuronal Aß. SIGNIFICANCE: There is a growing awareness that intraneuronal Aß is a key pathogenic pool of Aß involved in causing synapse dysfunction. Difficulties in detecting intraneuronal Aß are an insufficient reason for ignoring this critical pool of Aß.