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

Abstract

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.

Keywords: Alzheimer’s disease; GSK-3; Parkinson’s disease; combination therapy; feed-forward mechanisms.

Fig.1

GSK-3 regulates processes implicated in neurodegenerative disease. A) Under normal conditions GSK-3 is known to suppress processes that positivetly regulate cognition such as cholinergic, BDNF, and insulin signaling. GSK-3 also is involved in the suppression of gamma frequency oscillations. The phosphorylation of tau, α-synuclein and presenilin are also mediated by GSK-3. B) Under pathological conditions GSK-3 activity is upregulated, increasing its negative influence on cholinergic, BDNF, and insulin signaling, and at the same time promoting phosphorylation events critical to the development of proteinopathies. Increased GSK-3 activity also induces oxidative stress and the onset of inflammatory processes. Positive regulation (red arrows) and negative regulation (blue arrows) of each pathway and/or process are shown. Changes in the overall activity of these pathways compared to normal conditions are represented by the solid arrows (increased activation) and dotted arrows (decreased activation). AChR, acetylcholine receptor; BDNF, brain-derived neurotrophic factor; GSK-3β, glycogen synthase kinase-3β; IGF-1, insulin growth factor 1; TrkB, tropomyosin receptor kinase B; TrkB.T1, truncated tropomyosin receptor kinase.

Fig.2

Pathogenic feedforward loops in Alzheimer’s disease converge on GSK-3. In AD, several cellular, and bidirectional, processes work in concert to increase GSK-3 activity. These include deficits in cholinergic, BDNF/TrkB, and insulin or IGF-1 signaling, mitochondrial dysfunction leading to oxidative stress, and production of Aβ oligomers. This increase in GSK-3 activity further suppresses cholinergic, BDNF/TrkB, and the insulin/IGF-1 signaling pathways, and additionally promotes tau hyperphosphorylation and inflammation, and the disruption of gamma synchrony. The production of Aβ oligomers also increases due to GSK-3-mediated presenilin phosphorylation. Together these processes contribute to the onset of dementia. Positive regulation (red arrows) and negative regulation (blue arrows) of each pathway and/or process are shown. Changes in the overall activity of these pathways compared to normal conditions are represented by the solid arrows (increased activation) and dotted arrows (decreased activation). Aβ, amyloid-β; AChR, acetylcholine receptor; BDNF, brain-derived neurotrophic factor; GSK-3β, glycogen synthase kinase-3β; IGF-1, insulin growth factor 1; NFTs, neurofibrillary tangles; TrkB, tropomyosin receptor kinase B; TrkB.T1, truncated tropomyosin receptor kinase.

Fig.3

Pathogenic feedforward loops in Parkinson’s disease converge on GSK-3. In PD increased GSK-3 activity can arise as a result of deficits in cholinergic, BDNF/TrkB, and insulin or IGF-1 signaling, and mitochondrial dysfunction leading to oxidative stress. Consequently, increased GSK-3 activity results in enhanced tau and α-synuclein phosphorylation leading to proteinopathy, and induces inflammatory responses. GSK-3 activation also has additional impacts on oxidative stress. Positive regulation (red arrows) and negative regulation (blue arrows) of each pathway and/or process are shown. Changes in the overall activity of these pathways compared to normal conditions are represented by the solid arrows (increased activation) and dotted arrows (decreased activation). AChR, acetylcholine receptor; BDNF, brain-derived neurotrophic factor; GSK-3β, glycogen synthase kinase-3β; IGF-1, insulin growth factor 1; NFTs, neurofibrillary tangles; TrkB, tropomyosin receptor kinase B; TrkB.T1, truncated tropomyosin receptor kinase.