Sex differences in hippocampal ß-amyloid accumulation in the triple-transgenic mouse model of Alzheimer's disease and the potential role of local estrogens.

Introduction: Epidemiological studies show that women have a higher prevalence of Alzheimer's disease (AD) than men. Peripheral estrogen reduction during aging in women is proposed to play a key role in this sex-associated prevalence, however, the underlying mechanism remains elusive. We previously found that transcription factor early growth response-1 (EGR1) significantly regulates cholinergic function. EGR1 stimulates acetylcholinesterase (AChE) gene expression and is involved in AD pathogenesis. We aimed to investigate whether the triple-transgenic AD (3xTg-AD) mice harboring PS1 M146V , APP Swe , and Tau P301L show sex differences in ß-amyloid (Aß) and hyperphosphorylated tau (p-Tau), the two primary AD hallmarks, and how local 17ß-estradiol (E2) may regulate the expression of EGR1 and AChE. Methods: We first sacrificed male and female 3xTg-AD mice at 3-4, 7-8, and 11-12 months and measured the levels of Aß, p-Tau, EGR1, and AChE in the hippocampal complex. Second, we infected SH-SY5Y cells with lentivirus containing the amyloid precursor protein construct C99, cultured with or without E2 administration we measured the levels of extracellular Aß and intracellular EGR1 and AChE. Results: Female 3xTg-AD mice had higher levels of Aß compared to males, while no p-Tau was found in either group. In SH-SY5Y cells infected with lentivirus containing the amyloid precursor protein construct C99, we observed significantly increased extracellular Aß and decreased expression of intracellular EGR1 and AChE. By adding E2 to the culture medium, extracellular Aß(l-42) was significantly decreased while intracellular EGR1 and AChE expression were elevated. Discussion: This data shows that the 3xTg-AD mouse model can be useful for studying the human sex differences of AD, but only in regards to Ap. Furthermore, in vitro data shows local E2 may be protective for EGR1 and cholinergic functions in AD while suppressing soluble Aß(1-42) levels. Altogether, this study provides further in vivo and in vitro data supporting the human epidemiological data indicating a higher prevalence of AD in women is related to changes in brain estrogen levels.

Sex differences in the neuropathological hallmarks of Alzheimer's disease: focus on cognitively intact elderly individuals.

AIMS: Women are more vulnerable to Alzheimer's disease (AD) than men. We investigated (i) whether and at what age the AD hallmarks, that is, ß-amyloid (Aß) and hyperphosphorylated Tau (p-Tau) show sex differences; and (ii) whether such sex differences may occur in cognitively intact elderly individuals. METHODS: We first analysed the entire post-mortem brain collection of all non-demented 'controls' and AD donors from our Brain Bank (245 men and 403 women), for the presence of sex differences in AD hallmarks. Second, we quantitatively studied possible sex differences in Aß, Aß42 and p-Tau in the entorhinal cortex of well-matched female (n = 31) and male (n = 21) clinically cognitively intact elderly individuals. RESULTS: Women had significantly higher Braak stages for tangles and amyloid scores than men, after 80 years. In the cognitively intact elderly, women showed higher levels of p-Tau, but not Aß or Aß42, in the entorhinal cortex than men, and a significant interaction of sex with age was found only for p-Tau but not Aß or Aß42. CONCLUSIONS: Enhanced p-Tau in the entorhinal cortex may play a major role in the vulnerability to AD in women.

Quantification of Tyrosine Hydroxylase and ErbB4 in the Locus Coeruleus of Mood Disorder Patients Using a Multispectral Method to Prevent Interference with Immunocytochemical Signals by Neuromelanin.

The locus coeruleus (LC) has been studied in major depressive disorder (MDD) and bipolar disorder (BD). A major problem of immunocytochemical studies in the human LC is interference with the staining of the immunocytochemical end-product by the omnipresent natural brown pigment neuromelanin. Here, we used a multispectral method to untangle the two colors: blue immunocytochemical staining and brown neuromelanin. We found significantly increased tyrosine hydroxylase (TH) in the LC of MDD patients-thus validating the method-but not in BD patients, and we did not find significant changes in the receptor tyrosine-protein kinase ErbB4 in the LC in MDD or BD patients. We observed clear co-localization of ErbB4, TH, and neuromelanin in the LC neurons. The different stress-related molecular changes in the LC may contribute to the different clinical symptoms in MDD and BD.