How Amyloid-beta Forms Suggests New Strategies for Preventing, Treating Alzheimer's Disease
- Generation of amyloid-ß (Aß) has long been known to be a key event in the pathogenesis of Alzheimer's disease, but how Aß forms in axons has been unclear
- Previous research at Massachusetts General Hospital showed that a process called palmitoylation targets amyloid precursor protein (APP) to "lipid rafts" where it is more easily cleaved by ß-secretase to form Aß
- This study pinpointed mitochondria-associated endoplasmic reticulum membranes (MAMs), a specialized type of lipid raft, as the sites where palmitoylated APP (palAPP) is localized in axons and neuronal processes
- Antagonism of the sigma-1 receptor (S1R; one of the proteins enriched in MAMs) decreased Aß production exclusively in axons and neuronal processes, and agonism increased Aß production
- These data strongly suggest that targeting MAM-associated palAPP in axons (for example, by targeting S1R) is a therapeutic strategy to alleviate Aß pathology and thereby stop or slow the pathogenesis of Alzheimer's disease
The generation of amyloid-β (Aβ) has long been known to be a key event in the pathogenesis of Alzheimer's disease, and about 40% of neuronal Aβ production takes place in axons. Exactly how Aβ forms in axons has been unclear, though.
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As part of investigating this question, researchers at Massachusetts General Hospital previously made a crucial observation about amyloid protein precursor (APP), which when cleaved by β-secretase and γ-secretase yields Aβ. In The Journal of Neuroscience, they reported that a process called palmitoylation targets APP to "lipid rafts" (subcellular lipid-rich microdomains) where it is more easily cleaved by β-secretase.
Building on that work, Mass General's Raja Bhattacharyya, PhD, instructor in neurology, Dora M. Kovacs, PhD, associate professor of neurology and investigator at the Mass General Research Institute, Rudolph E. Tanzi, PhD, co-director of the McCance Center for Brain Health and vice-chair (research) of the Department of Neurology, and colleagues have now pinpointed which lipid rafts are involved. Moreover, in Cell Reports they describe various ways of interfering with β-secretase cleavage of palmitoylated APP (palAPP)—suggesting pharmaceutical strategies for reducing Aβ production in axons.
Identifying the Sites
The researchers observed that palAPP was primarily localized to mitochondria-associated endoplasmic reticulum membranes (MAMs), a specialized type of lipid raft. This was true both in mouse brains and in human neuronal progenitor cells expressing APP with familial Alzheimer's disease mutations.
MAMs contain APP and γ-secretase, and their activity is significantly increased in fibroblasts from patients with Alzheimer's disease. Even more intriguingly, MAMs are enriched in certain proteins being investigated as drug targets in Alzheimer's disease, including the sigma-1 receptor (S1R).
Effects of Altering MAM Levels and Activity
The researchers then studied two approaches to downregulating MAM assembly: gene therapy and an S1R antagonist. With both they observed the following effects exclusively in axons and neuronal processes:
- Greatly decreased levels of palAPP
- Reduction in the stability of palAPP and its trafficking to the cell surface
- Decreased β-secretase cleavage of palAPP
- Reduced production of Aβ
An S1R agonist had the opposite effects, including increased β-secretase cleavage of palAPP and increased Aβ production.
These data strongly suggest that targeting MAM-associated palAPP in axons (for example, by targeting S1R) is a therapeutic strategy to alleviate Aβ pathology and thereby stop or slow the pathogenesis of Alzheimer's disease.
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