Alzheimer Disease And Decrease In Estrogen Levels
Alzheimer Disease

Author: Matteo Filardo
Date: 12/12/2012


Is Alzheimer Disease Related To The Decrease In Estrogen Levels?


Alzheimer’s is a degenerative disease which affects the central nervous system and which is considered a form of dementia. This condition is due to the death of neural cells in the brain, which is caused in turn by the deposition of β-amyloid plates among the neurons: this protein stimulates the fusion of the cells, leading to the consequent impossibility in transmitting nervous signals. Another feature due to the formation of the plates is a massive activation of the immune response: macrophages and neutrophils reach the damaged tissue and produce inflammatory cytokines (like IL or TNF-α), which brings cells to apoptosis.
Alzheimer's disease

The protein β-amyloid is an intermediate product in APP (= Amyloid Precursor Protein) metabolism. APP is an integral membrane protein expressed in many tissues, and involved in mechanisms of synaptic plasticity in neurons. There are several kinds of existing isoforms, which have a length range from 365 to 770 aa, but all of them are different splicing products of the same gene on the chromosome 21.
It has been demonstrated that APP is continuously degraded in a series of fine-regulated steps in way to prevent, in normal conditions, the deposition of intermediate products like β-amyloid itself:

  • The first step, catalyzed by the β-secretase, is the cleavage of a C-terminal portion of 12KDa from the amyloid precursor
  • The remaining part of the protein loses another C-terminal portion to work of Ƴ-secretase: the product of this cut is β-amyloid (Aβ)
  • Normally Aβ is divided in two portions, sAPPα and C38, by the action of α-secretase; the end of the process is the reduction of C38 in p3 by the Ƴ-secretase

Many causes in this pathway may be responsible for the onset of Alzheimer’s: single nucleotide mutations on APP or inefficiency of one of the form of secretase (especially the α-secretase) can be considered risk factors or directly responsible for the deposition of β-amyloid plates.
The amyloid precursor protein: beyond amyloid, 2006

Nevertheless, not always the deposition of the protein in neural tissue brings about the disease in an immediate way. Our cells control single phenomena with a wide range of molecular pathway, so if only one among them fails it can be replaced by other similar ways: it counts also for Alzheimer’s disease, or more precisely for the toxic effect of Aβ.
In fact, β-amyloid acts with a various effect on neural cells: some of the involved molecular processes are still unknown; yet we know for sure that this protein activates pro-apoptotic signaling, activating Ask1 (= Apoptosis signal regulated kinase). The strict relationship between Aβ and Ask1 can be demonstrated using the cytosolic transmigration of death-protein Daxx as an indicator, because Daxx production depends on Ask activation.

Estrogens And Alzheimer's Disease

The relationship between aging and risk for Alzheimer’s disease it is considered as an axiom; what is not considered so clear is the reason why this linkage exists.
A significant normal age change known to result in tissue-specific dysfunction is the depletion of sex hormones: both estrogens and androgens exert a wide range of protective actions that improve multiple aspects of neural health. Significant studies and statistical evidence proved that in women the risk for Alzheimer is bigger and that the onset of the disease is earlier than in men: in women, menopause results in a relatively rapid loss of estradiol and progesterone; in men, aging is associated with a comparatively gradual yet significant decrease in testosterone.
Sex hormones, aging, and Alzheimer's disease, 2012

Analyzing this first data, it can be useful to focus on the effects of estrogens and menopause in women, since they are much more at risk for the disease than men.
For long time many studies have failed to report a precise estrogen protective effect from Alzheimer’s disease; on the other hand some other studies seem to demonstrate that estrogens themselves where involved in neurodegenerative phenomena. A harsh debate about the real effect of estrogens is still held in scientific community, but fortunately the new development in research permitted to have clear and definitive pieces of information about the molecular role of estrogens in neuropathology.

ASK1 pathway

Estrogen was shown to promote neuronal survival against several neurotoxic insults including β-amyloid (Aβ). The proposed mechanism includes the activation of the mitogen activated protein kinase/extracellular signal-regulated kinase (Mapk/Erk), phosphatidylinositol 3-kinase/Akt pathways and the upregulation of antiapoptotic proteins: in fact, estrogen can protect cells against Aβ toxicity by inhibiting the Ask1 cascade or by modulating Trx1.
The activation of Estrogen Receptor (ER), which can be recreated in vitro using estradiol, activates Akt signaling, which directly inhibits Ask1 pro-apoptotic pathway; the same effect can be produced by the modulation of Trx-1 . The final effect can be monitored measuring Daxx decreasing levels in the cells, which demonstrate the decrease of Ask signaling.
This demonstrates the protective role of estrogens against β-amyloid toxicity.
Ras-Raf-MEK-ERK-MAPK pathway
Estrogen protects against amyloid-β toxicity by estrogen receptor α-mediated inhibition of Daxx translocation, 2011


Matrix metalloproteinases (MMP) -2 and -9 are involved in Aβ degradation induced by estrogen. The production of MMP promoted by estrogens was demonstrated in an “in vitro” study on human neuroblastoma cells in the 2012:
“In SH-SY5Y human neuroblastoma cells, 17β-estradiol (17β-E2) increases mRNA and intracellular protein expression of MMP-2 and -9, as well as the levels of the active forms of both enzymes released in the medium. Specificity of the effect is proved by prevention with the estrogen receptor (ER) antagonist ICI 182,780 (1 μM) and involvement of the ERα subtype is confirmed by the use of selective ERα or ERβ agonists (PPT, DPN) and antagonists (MPP, PHTPP). 17β-E2 significantly increases the degradation of Aβ, either transferred with the conditioned medium of H4-APPSw human neuroglioma cells, engineered to overproduce Aβ(1-40) and Aβ(1-42), or exogenously added as 2 μM Aβ(1-42)”
This abstract demonstrates that MMP -2 and -9, whose production is promoted by estrogens, are able to control the formation of β-amyloid plates and to degrade them.
Estrogen activates matrix metalloproteinases-2 and -9 to increase beta amyloid degradation, 2012


These recent but significant studies are able to show the protective role of estrogens in β-amyloid synthesis, degradation and toxic effect. This abstract can lead to important explanations about the linkage between age and Alzheimer’s, and about the earlier onset of the disease in women: in menopause there is a rapid loss of estrogens, which means the immediate removal of the hormone’s protective effect on neural cells. Without the inhibition of the MMP, Aβ plates can develop, and their toxic effect is not counterbalanced by Akt and Trx; this situation amplifies the risk to develop Alzheimer’s disease. These studies may help in the development of a “hormone therapy” in menopausal period, which can prevent the unhealthy estrogens’ levels decrease with the administration of estradiol.

Unfortunately, not all the scientists agree on the neuroprotective effect given by estrogen, or on the possible use of a hormonal therapy: the old belief which gave estrogens a degenerative effect is still deep-rooted, and the long-time effects of a hormone therapy are still unknown.
Nevertheless, we can hope in a big step forward in the near future: finding a definitive demonstration of the relationship between Alzheimer’s and sex hormones can lead us to an efficient therapy for this neurodegenerative disease, and bring us some steps closer to a definitive treatment.
Long term hormone therapy for perimenopausal and postmenopausal women, 2009

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