The multifunctional mitochondrial enzyme 17β-hydroxysteroid dehydrogenase type 10 (HSD10) plays an important role in the pathology of several diseases, of which Alzheimer's disease (AD) is the most debated. HSD10 overexpression and its interplay with amyloid-β peptide (Aβ) are considered a factor contributing to mitochondrial damage and neuronal stress observed in AD patients. This study confirms that individual overexpression of HSD10 or APP (amyloid precursor protein that gives rise to Aβ) leads to cytotoxicity, and both pathological conditions are linked to mitochondrial damage. However, the metabolic changes caused by these two overexpressions significantly differ, particularly in their effect on the tricarboxylic acid cycle and β-oxidation. Furthermore, the enzymatic activity of HSD10 is identified as the primary factor of HSD10 cytotoxicity, which is significantly exacerbated in an Aβ-rich environment and can be partially reversed by HSD10 inhibitors. Notably, a previously published and competitive benzothiazole inhibitor was effective in restoring the viability of HSD10 overexpressing cells alone and in an Aβ-rich environment, implying the potential benefit of HSD10 inhibitors in mitochondrial diseases and/or AD treatment.

Immunotherapy of Alzheimer’s disease (AD) is a promising approach to reduce the accumulation of amyloid-beta (Aβ), a critical event in the onset of the disease. Targeting the group II metabotropic glutamate receptors, mGlu2 and mGlu3, could be important in controlling Aβ production, although their respective contribution remains unclear due to the lack of selective tools. Here, we show that enhancing mGlu2 receptor activity increases Aβ 1-42 peptide production whereas activation of mGlu3 has no effect. We show that such a difference likely results from the direct interaction of APP with mGlu3, but not with mGlu2 receptors, that prevents APP amyloidogenic cleavage and Aβ 1-42 peptides production. We then show that chronic treatments of the AD model 5xFAD mice with a brain-penetrating mGlu2-potentiating nanobody accelerated amyloid aggregation and exacerbated memory deficits, but had no effect in control mice. Our results confirm that a selective mGluR2 activation exacerbates AD disease development, suggesting that therapeutic benefices could be obtained with blockers of this receptor. Our study also provides the proof-of-concept that chronic administration of nanobodies targeting neuroreceptors can be envisioned to treat brain diseases.

Down syndrome (DS) is caused by the triplication of chromosome 21 and is the most common chromosomal disorder in humans. Those individuals with DS who live beyond age 40 y develop a progressive dementia that is similar to Alzheimer's disease (AD). Both DS and AD brains exhibit numerous extracellular amyloid plaques composed of Aβ and intracellular neurofibrillary tangles composed of tau. Since AD is a double-prion disorder, we asked if both Aβ and tau prions feature in DS. Frozen brains from people with DS, familial AD (fAD), sporadic AD (sAD), and age-matched controls were procured from brain biorepositories. We selectively precipitated Aβ and tau prions from DS brain homogenates and measured the number of prions using cellular bioassays. In brain extracts from 28 deceased donors with DS, ranging in age from 19 to 65 y, we found nearly all DS brains had readily measurable levels of Aβ and tau prions. In a cross-sectional analysis of DS donor age at death, we found that the levels of Aβ and tau prions increased with age. In contrast to DS brains, the levels of Aβ and tau prions in the brains of 37 fAD and sAD donors decreased as a function of age at death. Whether DS is an ideal model for assessing the efficacy of putative AD therapeutics remains to be determined.