Pathogenic Feed-Forward Mechanisms in Alzheimer’s and Parkinson’s Disease Converge on GSK-3

Alzheimer’s disease (AD) and Parkinson’s disease (PD) share many commonalities ranging from signaling deficits such as altered cholinergic activity, neurotrophin and insulin signaling to cell stress cascades that result in proteinopathy, mitochondrial dysfunction and neuronal cell death. These pathological processes are not unidirectional, but are intertwined, resulting in a series of feed-forward loops that worsen symptoms and advance disease progression. At the center of these loops is glycogen synthase kinase-3 (GSK-3), a keystone protein involved in many of the multidirectional biological processes that contribute to AD and PD neuropathology. Here, a unified overview of the involvement of GSK-3 in the major processes involved in these diseases will be presented. The mechanisms by which these processes are linked will be discussed and the feed-forward pathways identified. In this regard, this review will put forth the notion that combination therapy, targeting these multiple facets of AD or PD neuropathology is a necessary next step in the search for effective therapies.