Blocked Endosome De-acidification Prevents Amyloid Plaque Formation

The apolipoprotein E E4 allele of the APOE gene is the strongest genetic factor so far discovered for late-onset Alzheimer disease (LOAD). Previous studies have provided evidence that apoE influenced Alzheimer disease (AD) in large part by affecting amyloid beta (Abeta) aggregation and clearance; however, the molecular mechanism underlying these findings remains largely unknown.

Available evidence suggests that the root cause for this increased risk is a trafficking defect at the level of the early endosome. ApoE4 differs from the most common ApoE3 isoform by a single amino acid that increases its isoelectric point and promotes unfolding of ApoE4 upon endosomal vesicle acidification. Endosomes comprise three different compartments: early endosomes, late endosomes, and recycling endosomes. They are distinguished by the time it takes for endocytosed material to reach them, and by various protein markers. They also have different morphology. Once endocytic vesicles have uncoated, they fuse with early endosomes. Early endosomes then mature into late endosomes by becoming increasingly acidic before fusing with lysosomes.

Investigators at the University of Texas Southwestern Medical Center (Dallas, USA) reported in the October 30, 2018, online edition of the journal eLife that pharmacological and genetic inhibition of NHE6, the primary proton leak channel in the early endosome (which tends to make the endosome less acidic), in mice completely reversed the ApoE4-induced recycling block of the ApoE receptor and glutamate receptors that were regulated by, and co-endocytosed in a complex with, the ApoE receptor. Moreover, NHE6 inhibition restored modulation of excitatory synapses that was impaired by ApoE4.

“The beauty of NHE inhibitors is that these are small molecules that can be produced inexpensively and thus made widely available, in contrast to the more elaborate antibody-based therapies that are currently being evaluated in clinical trials. A simple pill could someday neutralize the risk of late-onset Alzheimer’s disease just as readily available statins are able to reduce the risk of cardiovascular disease,” said senior author Dr. Joachim Herz, professor of molecular genetics at the University of Texas Southwestern Medical Center. “Our approach in this study was to stop the overall degeneration process earlier; that is, before the formation of these aggregates. If we can negate the ApoE4 process early, we may be able to prevent late-onset Alzheimer’s altogether for many people so that they will never get sick."

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University of Texas Southwestern Medical Center