Polymorphisms in the
            <i>CYP19</i>
            gene confer increased risk for Alzheimer disease

Iivonen, Susan; Corder, Elizabeth H.; Lehtovirta, Maarit; Helisalmi, Seppo; Mannermaa, Arto; Vepsäläinen, Saila; Hänninen, Tuomo; Soininen, Hilkka; Hiltunen, Mikko

doi:10.1212/01.wnl.0000118208.16939.60

Cited by 73 publications

(17 citation statements)

References 47 publications

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“…Recent findings have suggested that BACE plays a critical role in AD neuropathogenesis (43). Consistent with these are our observations that BACE protein expression and enzyme activity, as well as A␤ 40 and A␤ 42 levels, are elevated in the brains of APP23͞Ar ϩ/Ϫ mice.…”

Section: Discussionsupporting

confidence: 91%

Brain estrogen deficiency accelerates Aβ plaque formation in an Alzheimer's disease animal model

Yue

Lu²,

Lancaster³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

334

306

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Much evidence indicates that women have a higher risk of developing Alzheimer's disease (AD) than do men. The reason for this gender difference is unclear. We hypothesize that estrogen deficiency in the brains of women with AD may be a key risk factor. In rapidly acquired postmortem brains from women with AD, we found greatly reduced estrogen levels compared with those from age-and gender-matched normal control subjects; AD and control subjects had comparably low levels of serum estrogen. We examined the onset and severity of AD pathology associated with estrogen depletion by using a gene-based approach, by crossing the estrogen-synthesizing enzyme aromatase gene knockout mice with APP23 transgenic mice, a mouse model of AD, to produce estrogen-deficient APP23 mice. Compared with APP23 transgenic control mice, estrogen-deficient APP23 mice exhibited greatly reduced brain estrogen and early-onset and increased ␤ amyloid peptide (A␤) deposition. These mice also exhibited increased A␤ production, and microglia cultures prepared from the brains of these mice were impaired in A␤ clearance͞degradation. In contrast, ovariectomized APP23 mice exhibited plaque pathology similar to that observed in the APP23 transgenic control mice. Our results indicate that estrogen depletion in the brain may be a significant risk factor for developing AD neuropathology.amyloid deposition ͉ aromatase ͉ transgenic animal N europathological hallmarks of Alzheimer's disease (AD) include significant deposition of extracellular ␤ amyloid peptide (A␤) and presence of neurofibrillary tangles in the brain (1). A␤ is derived from the two-step enzymatic processing of amyloid precursor protein (APP) in which ␤-secretase (BACE) cleaves the ␤-site of APP to release the N terminus of A␤, and the ␥-secretase protein complex cleaves the ␥-site of APP to release the C terminus of A␤ (2, 3). Overproduction and progressive deposition of A␤ are known to underlie, in part, A␤ plaque formation, a key pathologic feature of AD. The initial cleavage of APP by BACE is critical for A␤ associated with AD neuropathology (4). Recent studies have shown that BACE activity increases with age and is elevated in AD brains (5, 6).Impaired A␤ clearance and͞or degradation may also contribute to A␤ plaque formation. Our previous findings support this hypothesis: Microglia isolated from AD brains have impaired phagocytic activity, leading to reduced A␤ clearance (7). Other groups have found that cytoplasmic A␤ granules in the plaque-associated glia and microglia participate in the clearance of A␤ in A␤-immunized AD patients and APP transgenic mice (8, 9).Two enzymes are involved in A␤ degradation and clearance: insulin-degrading enzyme (IDE) and neprilysin (NEP). IDE is expressed in high concentrations in the brain. Besides degrading insulin and several regulatory peptides, IDE also degrades the intracellular domain of APP and is responsible for degrading and clearing A␤ from the brain (10, 11). Indeed, genetic linkage studies have shown that late-onset AD loci on chromosome 1...

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Section: Discussionsupporting

confidence: 91%

Brain estrogen deficiency accelerates Aβ plaque formation in an Alzheimer's disease animal model

Yue

Lu²,

Lancaster³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

334

306

View full text Add to dashboard Cite

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“…In humans, postmortem studies have also shown that aromatase expression in the brain and aromatase genotype are linked to Alzheimer's disease (Ishunina et al, 2005, Livonen et al, 2004, Huang et al, 2006, Hiltunen et al, 2006) and autism (Sarachana et al, 2011, 2013)…”

Section: Current Limitations and Future Directionsmentioning

confidence: 99%

In vivo visualization of aromatase in animals and humans

Biegon

2016

Frontiers in Neuroendocrinology

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Aromatase catalyzes the last and obligatory step in the biosynthesis of estrogens across species. In vivo visualization of aromatase can be performed using positron emission tomography (PET) with radiolabeled aromatase inhibitors such as [11C]vorozole. PET studies in rats, monkeys and healthy human subjects demonstrate widespread but heterogeneous aromatase availability in brain and body, which appears to be regulated in a species, sex and region-specific manner. Thus, aromatase availability is high in brain amygdala and in ovaries of all species examined to date, with males demonstrating higher levels than females in all comparable organs. However, the highest concentrations of aromatase in the human brain are found in specific nuclei of the thalamus while the highest levels in rats and monkeys are found in the amygdala. Regional brain aromatase availability is increased by androgens and inhibited by nicotine. Future studies may improve diagnosis and treatment in brain disorders and cancers overexpressing aromatase.

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“…Subjects with the CYP 19(aromatase) polymorphism with the long allele variant (A6 or 8 r allele) have higher estrogen levels and lower androgen levels. Interestingly, intragenic single nucleotide polymorphisms (SNPs) in CYP19 have been found to associate with AD [47]. This could suggest that protective mechanisms are in place.…”

Section: Interactions Of the Cyp19 (Aromatase) Polymorphism And T Levelsmentioning

confidence: 99%

Increasing Testosterone Levels and Effects on Cognitive Functions in Elderly Men and Women: A Review

Hogervorst¹,

Bandelow²,

Moffat³

2005

CDTCNSND

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Low testosterone (T) levels may predispose to Alzheimer disease (AD), but it is unclear whether this is a co-morbid effect due to cachexia, subclinical hyperthyroidism or other co-morbidity. The biological plausibility for potential protective effects of T on brain functions is substantial. In addition, higher levels of gonadotropins found in older cases with AD suggest that low levels of T are not due to brain degeneration and that the hypothalamic-pituitary-gonadal (HPG) axis is still intact. Men genetically at risk for AD were also already found to have lower levels of T. However, despite having lower levels of T, women do not show accelerated cognitive decline with age when compared to men. In addition, castration has not necessarily shown a decline in cognitive functions; some studies even found improvement of memory recall. Age may be an important factor when assessing optimal levels of T and several studies suggest that free or bioavailable T may be a better marker than total T levels when investigating associations of androgen activity with cognitive function. Small-scale T intervention trials in elderly men with and without dementia suggest that some cognitive deficits may be reversed, at least in part, by short term T supplementation. Age and prior hypogonadism may play an important role in therapy success and these factors should be investigated in more detail in future large scale randomized controlled studies. For elderly women, T treatment does not seem to have additional benefits over estrogen treatment for postmenopausal complaints and cognitive decline and may increase cardiovascular disease.

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Polymorphisms in the CYP19 gene confer increased risk for Alzheimer disease

Abstract: Genetic variation in the brain aromatase gene may modify the risk for AD.

Cited by 73 publications

References 47 publications

Brain estrogen deficiency accelerates Aβ plaque formation in an Alzheimer's disease animal model

Brain estrogen deficiency accelerates Aβ plaque formation in an Alzheimer's disease animal model

In vivo visualization of aromatase in animals and humans

Increasing Testosterone Levels and Effects on Cognitive Functions in Elderly Men and Women: A Review

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