. Genetic targeting aromatase in male amyloid precursor protein transgenic mice down-regulates beta-secretase (BACE1) and prevents Alzheimer-like pathology and cognitive impairment. J Neurosci. 2010 May 26;30(21):7326-34. PubMed.

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  1. It is nice to see a paper that examines testosterone, as well as estradiol (E2). The data look compelling, although we and others have reported data that luteinizing hormone (LH) appears to be primarily responsible for modulating the processing of AβPP (Bowen et al., 2004 and supported by other studies, e.g., Berry et al., 2008; Lin et al., 2010), at least in female rodents. The suppression of β-secretase cleavage of AβPP and the decreased deposition of Aβ in the APP23/Ar+/- mouse, which has elevated testosterone levels, is therefore puzzling, since the Ar+/- mice (at least the females) have elevated serum LH concentrations (Britt et al., 2001).

    Our in vitro studies indicate that LH can upregulate AβPP processing towards the amyloidogenic pathway (Bowen et al., 2004), while Thornton and colleagues (see Berry et al., 2008) demonstrated that hCG (the fetal equivalent of LH that binds the same receptor) treatment to E2-implanted females significantly increased soluble Aβ40 and Aβ42 levels. Moreover, Lei and colleagues (see Lin et al., 2010) recently reported that ablation of the LH receptor (LHR) resulted in a significant reduction in amyloid load and total number of Aβ plaques in the hippocampus and cerebral cortex of male and female APPsw+/lhr-/- mice. These female mice also have elevated LH (which doesn’t signal via LHR), elevated follicle stimulating hormone (FSH), decreased E2 and decreased progesterone (P4), which doesn't explain sex steroid induced decreases in amyloidosis reported in this paper by Rena Li and colleagues. Male APPsw+/lhr-/- mice also have elevated LH (but can't signal as no LHR), elevated FSH, and suppressed testosterone, which also doesn't explain decreased amyloidosis reported by Li, but elevated E2, which could explain decreased amyloidosis. While male APPsw+/lhr-/- mice have suppressed testosterone and decreased amyloid load, the male APP23/Ar+/- mice have elevated testosterone and suppressed amyloid load, which is difficult to reconcile if Li’s conclusion is that testosterone regulates AβPP processing.

    There may be multiple possibilities to explain these contradictory results. Ultimately, it is likely that the ratio of sex steroids to LH is more important in determining the direction of AβPP processing. LH levels were not reported in ARKO mice on the APP23 background, or in lhr-/- mice on a APP23 background. It would be interesting to measure LH, testosterone, E2 and P4 levels of the ARKO mice on the APP23 background, and lhr-/- mice on a APP23 background, and then compare ratios among these animals (models/studies).

    References:

    . Luteinizing hormone, a reproductive regulator that modulates the processing of amyloid-beta precursor protein and amyloid-beta deposition. J Biol Chem. 2004 May 7;279(19):20539-45. PubMed.

    . Human chorionic gonadotropin (a luteinizing hormone homologue) decreases spatial memory and increases brain amyloid-beta levels in female rats. Horm Behav. 2008 Jun;54(1):143-52. PubMed.

    . Genetic ablation of luteinizing hormone receptor improves the amyloid pathology in a mouse model of Alzheimer disease. J Neuropathol Exp Neurol. 2010 Mar;69(3):253-61. PubMed.

    . The ovarian phenotype of the aromatase knockout (ArKO) mouse. J Steroid Biochem Mol Biol. 2001 Dec;79(1-5):181-5. PubMed.

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