Sex Hormone Decline and Amyloid β Synthesis, Transport and Clearance in the Brain

Abstract

Sex hormones (SH) are essential regulators of the central nervous system. The decline in SH levels along with ageing may contribute to compromised neuroprotection and set the grounds for neurodegeneration and cognitive impairments. In Alzheimer's disease, besides other pathological features, there is an imbalance between amyloid b (Ab) production and clearance, leading to its accumulation in the brain of older subjects. Ab accumulation is a primary cause for brain inflammation and degeneration, as well as concomitant cognitive decline. There is mounting evidence that SH modulate Ab production, transport and clearance. Importantly, SH regulate most of the molecules involved in the amyloidogenic pathway, their transport across brain barriers for elimination, and their degradation in the brain interstitial fluid. This review brings together data on the regulation of Ab production, metabolism, degradation and clearance by SH.

Pharmacological Mechanisms Underlying the Neuroprotective Effects of Alpinia oxyphylla Miq. on Alzheimer’s Disease

“…The cardinal neuropathological features of AD include extracellular accumulations of amyloid beta (Aβ) peptide [2], neurofibrillary tangles (NFTs) of hyper-phosphorylated tau proteins [3], neuropil threads, dystrophic neuritis [4,5], astrogliosis, microglial activation [6], and overall neurodegeneration of the brain [6][7][8]. Several hypotheses about cholinergic system dysfunction [9], Aβ deposits, oxidative stress [10], inflammatory pathways [11], calcium signaling dysfunction [12], hormone imbalance [13], and genetic components [14] have been considered to play important roles in the occurrence and development of AD, although the etiology of this disease is still not precisely known [15]. In addition, although several therapies have been used as compensation for the cholinergic neuronal loss and reduction or prevention of amyloid/tau aggregation and toxicity, such as gene therapy, vaccines, anti-inflammatory agents [16], cholesterol-lowering agents, anti-oxidants [17], and hormone therapy [18] for AD, these single targeted therapies have often been unsuccessful [19,20].…”

Age, Sex Hormones, and Circadian Rhythm Regulate the Expression of Amyloid-Beta Scavengers at the Choroid Plexus

“…As a key element in Aβ clearance routes, the CP maintains Aβ levels not only with the renewal of the CSF but also with the active secretion of several proteins involved in Aβ transport/degradation, such as apolipoprotein J (APOJ), gelsolin (GLS), and transthyretin (TTR) (reviewed in [ 8 ]). APOJ may bind, and gradually reduce, Aβ accumulation and aggregation, reducing amyloid fibrillogenesis and improving its clearance.…”

“…Particularly, in the CP, GLS is able to protect Aβ-induced cytoskeletal modifications [ 9 ]. Finally, TTR is able to bind Aβ preventing its aggregation and toxicity, but if sequestration fails, TTR is also capable of disrupting Aβ fibrils [ 8 ]. Considering all the above, once synthesized, these Aβ-related molecules are secreted into the CSF where they can form stable complexes with the Aβ peptide and hydrolyze it into less-neurotoxic fragments.…”

An exploratory investigation of brain-selective estrogen treatment in males using a mouse model of Alzheimer's disease

“…1). The mechanisms of E2’s effect on APP level may involve modulation of mRNA synthesis through alternative splicing (Thakur and Mani, 2005), induction of a rapid secretion of the protein via the mitogen-activated protein kinase pathway (Manthey et al, 2001), and stimulation of APP’s proteolysis through the non-amyloidogenic pathway (Duarte et al, 2016). By inhibiting APP trafficking to the trans-Golgi network, E2 may also reduce Aβ formation by decreasing the substrate pool for amyloidogenic degradation of the protein (Greenfield et al, 2002).…”