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Review
. 2014 Jul 28:6:176.
doi: 10.3389/fnagi.2014.00176. eCollection 2014.

Alzheimer's disease: relevant molecular and physiopathological events affecting amyloid-β brain balance and the putative role of PPARs

Juan M Zolezzi  1 , Sussy Bastías-Candia  1 , Manuel J Santos  2 , Nibaldo C Inestrosa  3
Affiliations
Review

Alzheimer's disease: relevant molecular and physiopathological events affecting amyloid-β brain balance and the putative role of PPARs

Juan M Zolezzi et al. Front Aging Neurosci. .

Abstract

Alzheimer's disease (AD) is the most common form of age-related dementia. With the expected aging of the human population, the estimated morbidity of AD suggests a critical upcoming health problem. Several lines of research are focused on understanding AD pathophysiology, and although the etiology of the disease remains a matter of intense debate, increased brain levels of amyloid-β (Aβ) appear to be a critical event in triggering a wide range of molecular alterations leading to AD. It has become evident in recent years that an altered balance between production and clearance is responsible for the accumulation of brain Aβ. Moreover, Aβ clearance is a complex event that involves more than neurons and microglia. The status of the blood-brain barrier (BBB) and choroid plexus, along with hepatic functionality, should be considered when Aβ balance is addressed. Furthermore, it has been proposed that exposure to sub-toxic concentrations of metals, such as copper, could both directly affect these secondary structures and act as a seeding or nucleation core that facilitates Aβ aggregation. Recently, we have addressed peroxisomal proliferator-activated receptors (PPARs)-related mechanisms, including the direct modulation of mitochondrial dynamics through the PPARγ-coactivator-1α (PGC-1α) axis and the crosstalk with critical aging- and neurodegenerative-related cellular pathways. In the present review, we revise the current knowledge regarding the molecular aspects of Aβ production and clearance and provide a physiological context that gives a more complete view of this issue. Additionally, we consider the different structures involved in AD-altered Aβ brain balance, which could be directly or indirectly affected by a nuclear receptor (NR)/PPAR-related mechanism.

Keywords: Aβ balance; blood-brain barrier; brain homeostasis; neurodegenerative disorders; nuclear receptors; systemic Aβ clearance.

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Figures

Figure 1
Figure 1
Aβ brain balance, a systemic event. Although the link between Aβ and AD has been known from decades, the importance of Aβ balance, as the result of clearance mechanisms along with brain Aβ production and influx events, has become important only recently. Moreover, the link between the Aβ brain levels and the involvement of brain adjacent tissues, such as the blood-brain barrier (BBB) or the ChP, as well as, with systemic alterations have been emerged as an interesting matter to examine. Indeed, recent studies have explored the potentialities of systemic interventions in order to reduce Aβ brain levels. Several studies have demonstrated that ApoE levels, the main Aβ chaperone within the brain, is a key element of Aβ brain removal and along with the BBB ApoE-related transporters account for almost the total Aβ brain clearance. Additional structures, such as the ChP, has also been demonstrated to play a key role in the Aβ removal from the brain to the CSF and to blood. At the basis of the Aβ brain clearance, emerge an Aβ sink established by the systemic excretion of the Aβ, a process carried out mainly by the liver and in less proportion by the kidneys. Whether normal or abnormal levels of Aβ production (increased APP or BACE expression, in the lipid rafts) the Aβ sink in the final Aβ brain balance is clearly critical. If an impaired systemic Aβ excretion due to failure of the liver or kidney, compromise the chances to properly reduce the blood Aβ charge, and additional elements, such as the RAGE, might start to act and inducing Aβ influx to the brain, starting or aggravates the Aβ accumulation. BBB, blood-brain barrier; ChP, Choroid plexus; ApoE, apolipoprotein E; APP, amyloid precursor protein; BACE, β-site APP cleaving enzyme; RAGE, receptor for advanced glycation end products.
Figure 2
Figure 2
APP processing, critical cellular choice. The main source of Aβ production within the brain are the neurons. Two proteolytic processing pathways of APP have been described with two clear outputs. The non-amyloidogenic pathway will lead to the final release of the p3 and sAPPα, a small peptide with still poorly understood cell function. The cleaving enzymes which act to produce the sAPPα are the α- and γ-secretase. On the other hand, the activity of the β- and γ-secretase leads to the formation of the sAPPβ and the Aβ, the main neurotoxic agent described in AD. The role of the BACE is out of question and it is considered the Aβ production rate limiting enzyme. Interestingly, the recent work of Singh et al. (2013) clearly indicates that external factors might influence the expression levels of BACE, suggesting the potential up-regulation of the amyloidogenic processing of the APP. In the same context, it have been recently proposed that the APP amyloidogenic processing machinery is located in the lipid rafts rich in cholesterol. The increased lipid content within the cells, for example, as a result of increased systemic lipids levels, might also influence which APP processing machinery will be prompted to act. sAPPα/β, soluble APP fragment α/β; p3, 3-KDa peptide; BACE, β-site APP cleaving enzyme.
Figure 3
Figure 3
Aβ balance, systemic overview. The main discussion regarding Aβ clearance has been centered at the brain level. Increased production and decreased removal from the brain certainly constitutes a highly relevant issue. The relevance of the BBB integrity or the Aβ excretion through the ChP are now recognized as key elements regarding Aβ brain levels. However, a growing body of evidence suggest the critical role of systemic final excretion of Aβ in AD. In this regard, expression levels of LRP 1 within the liver and hepatocyte are critical for the appropriate liver excretion of Aβ, which could account for up to the 60% of the total systemic Aβ clearance. On the other hand, even when not fully understood, kidneys not only play an important role in systemic Aβ clearance, but the precise renal function might account for blood vessels health and appropriate blood pressure levels which could influence the BBB integrity and its functionality. LRP, low density lipoprotein-related receptor protein; sLRP-Aβ, soluble LRP bond to Aβ; BCSFB, brain-cerebrospinal fluid barrier; ChP, choroid plexus.
Figure 4
Figure 4
PPARs, potential for systemic Aβ clearance. PPARs are a complex subfamily of NRs. Several PPARs agonists have been studied under different physiological and pathological conditions, and numerous effects have been reported for this group of drugs in several organs. Central nervous system (CNS), liver and kidneys are some of the tissues which have demonstrated to respond to PPAR agonist treatments. In this regard, the present scheme summarizes part of the current knowledge relative to PPARs agonists and the potential that they might exert in different organs regarding the Aβ systemic clearance. Of course, much research is needed in order to properly address the importance of PPARs as therapeutic agents, but the approach presented here suggest the study of new therapeutic strategies including additional intervention levels.
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