Amyloid β Induces the Morphological Neurodegenerative Triad of Spine Loss, Dendritic Simplification, and Neuritic Dystrophies through Calcineurin Activation

Abstract

Amyloid ␤ (A␤)-containing plaques are surrounded by dystrophic neurites in the Alzheimer's disease (AD) brain, but whether and how plaques induce these neuritic abnormalities remain unknown. We tested the hypothesis that soluble oligomeric assemblies of A␤, which surround plaques, induce calcium-mediated secondary cascades that lead to dystrophic changes in local neurites. We show that soluble A␤ oligomers lead to activation of the calcium-dependent phosphatase calcineurin (CaN) (PP2B), which in turn activates the transcriptional factor nuclear factor of activated T cells (NFAT). Activation of these signaling pathways, even in the absence of A␤, is sufficient to produce a virtual phenocopy of A␤-induced dystrophic neurites, dendritic simplification, and dendritic spine loss in both neurons in culture and in the adult mouse brain. Importantly, the morphological deficits in the vicinity of A␤ deposits in a mouse model of AD are ameliorated by CaN inhibition, supporting the hypothesis that CaN-NFAT are aberrantly activated by A␤ and that CaN-NFAT activation is responsible for disruption of neuronal structure near plaques. In accord with this, we also detect increased levels of an active form of CaN and NFATc4 in the nuclear fraction from the cortex of patients with AD. Thus, A␤ appears to mediate the neurodegeneration of AD, at least in part, by activation of CaN and subsequent NFAT-mediated downstream cascades.

Reactive Glia not only Associates with Plaques but also Parallels Tangles in Alzheimer's Disease

“…such as cyclosporine and FK-506 (tacrolimus), can revert these A␤-related pathological changes both in vitro and in vivo and ameliorate both the neuropathological features and the memory deficits of AD mouse models. 26,[51][52][53] In summary, our findings indicate a major role of gliosis in the pathophysiological features of both amyloid plaques and NFTs, suggesting that glial cells might be proactive players linking A␤ with downstream neurodegenerative events beyond their role in the initial steps of the amyloid cascade. The implications of these results for the development of imaging biomarkers and diseasemodifying drugs encourage further research.…”

“…48,49 Fibrillar and particularly oligomeric A␤ can aberrantly activate this molecular signaling pathway in glial cells 48,50 and neurons, causing the morphological triad of dystrophic neurites, dendritic simplification, and loss of dendritic spines, subsequently leading to cognitive impairment. [51][52][53] More important, Food and Drug Administration-approved and available calcineurin inhibitors, Figure 7. A model of the progression of AD-related pathological features in the temporal neocortex based on the present results.…”

Plaque-Associated Local Toxicity Increases over the Clinical Course of Alzheimer Disease

“…Plaque-associated dystrophic neurites are thought to be the result of the direct neurotoxic effect of Ab oligomers, 26 reactive oxygen species, 27 and the inflammatory milieu 28,29 that exist around dense-core plaques. There are many markers for plaque-associated dystrophic neurites, including amyloid precursor protein, phosphorylated neurofilament, ubiquitin, and phospho-tau.…”

Molecular Targets of Cannabidiol in Neurological Disorders

“…The NFAT pathway is a master regulator of the immune response and is inhibited by ciclosporin, but can also display antiapoptotic actions in neurons [203,204]. However, Aβ-induced neuritic damage, in an in vitro model, mimics the increased intracellular calcium often seen in neurodegenerative disorders and is associated with upregulation of the calcineurin-NFAT pathway, inhibition of this pathway, both in vivo and in vitro, can reverse markers of neurodegeneration [205]. Indeed, in the brains of patients with AD, increased nuclear NFAT is a common finding-and cognitive decline in this disease is associated with selective changes calcineurin/NFAT signaling.…”