Could Alzheimer's Disease Originate in the Periphery and If So How So?

Abstract

The classical amyloid cascade model for Alzheimer's disease (AD) has been challenged by several findings. Here, an alternative molecular neurobiological model is proposed. It is shown that the presence of the APOE ε4 allele, altered miRNA expression and epigenetic dysregulation in the promoter region and exon 1 of TREM2, as well as ANK1 hypermethylation and altered levels of histone post-translational methylation leading to increased transcription of TNFA, could variously explain increased levels of peripheral and central inflammation found in AD. In particular, as a result of increased activity of triggering receptor expressed on myeloid cells 2 (TREM-2), the presence of the apolipoprotein E4 (ApoE4) isoform, and changes in ANK1 expression, with subsequent changes in miR-486 leading to altered levels of protein kinase B (Akt), mechanistic (previously mammalian) target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3), all of which play major roles in microglial activation, proliferation and survival, there is activation of microglia, leading to the subsequent (further) production of cytokines, chemokines, nitric oxide, prostaglandins, reactive oxygen species, inducible nitric oxide synthase and cyclooxygenase-2, and other mediators of inflammation and neurotoxicity. These changes are associated with the development of amyloid and tau pathology, mitochondrial dysfunction (including impaired activity of the electron transport chain, depleted basal mitochondrial potential and oxidative damage to key tricarboxylic acid enzymes), synaptic dysfunction, altered glycogen synthase kinase-3 (GSK-3) activity, mTOR activation, impairment of autophagy, compromised ubiquitin-proteasome system, iron dyshomeostasis, changes in APP translation, amyloid plaque formation, tau hyperphosphorylation and neurofibrillary tangle formation.

Keywords: Alzheimer’s disease; Gene expression; Inflammation; Microglia; Mitochondria; Molecular neurobiology.

Fig. 1

The amyloid hypothesis. According to the current ‘amyloid cascade’ model of disease causation, Aβ overproduction stems from the disruption of homeostatic mechanisms that regulate the proteolytic cleavage of APP under physiological conditions. This model proposes that age-related, genetic, epigenetic and environmental factors collude to provoke a metabolic shift favouring the processing of APP by BACE1 and the intramembranous γ-secretase complex composed in part by presenilin-1 or presenilin-2, while simultaneously inhibiting the physiological, secretory pathway via α-secretase, which releases soluble APPα which precludes generation of Aβ. The net result is to enhance the production of the putatively neurotoxic Aβ₄₂ monomer at the expense of the putatively neuroprotective Aβ₄₀. The current version of the amyloid hypothesis claims that Aβ₄₂ accumulation into soluble oligomers is the primary driver of neuropathology, although the data allow for an independent or synergistic role for insoluble fibrils

Fig. 2

Physiological and pathological APP processing. APP is processed via two mutually exclusive pathways involving cleavage by β-secretase and α-secretase. Cleavage by the latter enzyme intersects the β-amyloid region, which eliminates the possibility of Aβ production and produces membrane-bound C83 protein and sAPPα which enters the cytosol. Subsequent processing of C83 by γ-secretase generates p3 and Aβ together with the amino-terminal APP intracellular domain (AICD). APP cleavage by β-secretase results in the production sAPPβ and C99. Further processing of C99 leads to the production of the AICD fragment and Aβ which forms oligomers and ultimately fibrils

Fig. 3

Iron homeostasis in neurones. Neurones and glial cells can uptake iron bound to transferrin (TBI), or bound to other molecules such as citrate and ATP secreted by astrocytes (NTBI). Neuronal uptake of TBI is enabled by the transferrin receptor located at the cell membrane and the uptake of NTBI in inflammatory conditions is probably enabled by DMT1. DMT1 and TfR1 complexes are internalised via endocytosis, ultimately resulting in the release of redox-active iron (Fe(II)) into the cytosol and the return of other molecules in the complexes to the plasma membrane. Once in the cytosol, Fe(II) can be utilised for various essential metabolic processes such as the synthesis of iron-sulphur proteins, or sequestrated by cytosolic ferritin and mitochondrial ferritin (FtMt), which offers protection against the advent of the Fenton reaction. Iron is removed from neurones by ferroportin, supported by the multi-copper-containing ferroxidase caeruloplasmin and sAPP, which both act to stabilise ferroportin at the cell surface

Fig. 4

Post-transcriptional control of iron homeostasis in neurones and glial cells. Binding of IRP1 and IRP2 to IRE in the 5′-UTR of mRNAs encoding ferritin and ferroportin represses translation, while binding of IRP1 and IRP2 to IRE in the 3′-UTR of mRNAs encoding TfR1 and DMT1 stabilises the mRNA resulting in efficient translation. In an environment of increasing oxidative stress, IRP2 is degraded while IRP1-mRNA binding is enhanced, which inhibits the synthesis of ferritin, ferroportin and APP while simultaneously upregulating the production DMT1 and TfR1. The cumulative effect of these activities is significantly increased iron