Amyloidogenesis and Neurotrophic Dysfunction in Alzheimer's Disease: Do They have a Common Regulating Pathway?

Abstract

The amyloid cascade hypothesis has predominately been used to describe the pathogenesis of Alzheimer's disease (AD) for decades, as Aβ oligomers are thought to be the prime cause of AD. Meanwhile, the neurotrophic factor hypothesis has also been proposed for decades. Accumulating evidence states that the amyloidogenic process and neurotrophic dysfunction are mutually influenced and may coincidently cause the onset and progress of AD. Meanwhile, there are intracellular regulators participating both in the amyloidogenic process and neurotrophic pathways, which might be the common original causes of amyloidogenesis and neurotrophic dysfunction. In this review, the current understanding regarding the role of neurotrophic dysfunction and the amyloidogenic process in AD pathology is briefly summarized. The mutual influence of these two pathogenesis pathways and their potential common causal pathway are further discussed. Therapeutic strategies targeting the common pathways to simultaneously prevent amyloidogenesis and neurotrophic dysfunction might be anticipated for the disease-modifying treatment of AD.

Keywords: Alzheimer’s disease; amyloid-β; amyloidogenesis; neurotrophic.

Figure 1

Hypothetical common pathogenesis and targets for Alzheimer’s disease. Amyloidogenic process and neurotrophic pathways are mutually inhibited. Original deficit in any of the two pathways may dysregulate the other one and mutually aggravate each other, or coordinately cause or deteriorate AD. Abnormal expression or activities of the regulators (brown and yellow boxes) result in the dysregulated expression or activities of the key proteins (pink boxes), leads to overloaded neurotoxicity and degraded neurotrophic effects, and finally, causes Alzheimer’s disease. Targeting these regulators (red dotted arrows)—including recover the expression levels or correcting the mutations via gene therapies or specific drugs, or modifying the activity to compensate for the dysfunction resulting from abnormal expression levels or mutation—might be effective strategies to treat AD.