Assoc. Prof. Evandro F. Fang and his team published a new hypothesis on AD in Ageing Research Reviews 2021. For full-text click here.

Proposed mechanism of the occurrence of the earliest AD pathology in entorhinal cortex (EC) L-II: linkages of impaired mitophagy which leads to impaired mitochondrial homeostasis, in Abeta and Tau pathologies are presented. (A) Immunofluorescently labeled reelin-positive neuronal population in L-II of rat EC. (B-C) Schematic representation of the signal transduction cascade generated by reelin under normal physiological conditions (B) vs AD (C). (B) Under normal conditions, including in young individuals, reelin is highly expressed. Reelin binds to lipoprotein receptors, such as ApoER2 and VLDLR, inducing activation of Disabled 1 (Dab1), an adapter protein. Activated Dab1 induces activation of Src family kinases (SFKs) that potentiate tyrosine phosphorylation of Dab1, which in turn activates Phosphoinositide 3-kinase (PI3K) and subsequently protein kinase B (PKB). PKB activation inhibits the activity of GSK3β, thereby reducing p-Tau and promoting microtubule stability. PKB also activates mTOR-dependent processes which promote the outgrowth of dendrites and balances mitochondrial biogenesis and autophagy. Changes of mTOR activity affect the activities of ULK1, AMPK, sirtuins (SIRTs), FOXOs, and NAD⁺. In addition, ApoER2-reelin complex is coupled to NMDAR signaling through PSD95. Reelin-activated SFK phosphorylates NMDAR and potentiates NMDAR-Ca²⁺ influx. Influx of Ca²⁺ activates the transcriptional regulator, CREB, through which expression of genes important for synaptic plasticity and neurite growth are potentiated. CREB-regulated genes encode proteins important for learning and memory. Astrocyte- and neuron-derived ApoEs bind to ApoER2 and are constitutively internalized. Upon reelin signaling, ApoER2 also undergoes endocytosis. In the cases of ApoE2 and ApoE3, ApoER2 is efficiently recycled to the cell membrane; this is impaired in the case of ApoE4. In healthy young individuals, mitophagy effectively clears damaged mitochondria, ensuring a healthy mitochondrial pool in the high-energy demanding axon terminals; this enables normal neuronal function and neuronal plasticity. Mitophagy also eliminates intracellular iAβ_1-42 and pathological Tau proteins. (C) Ageing is the primary driver of AD with multiple molecular mechanisms involved, including age-dependent reduction of reelin and impaired mitophagy (also autophagy). In prodromal AD, reduced reelin in the EC L-II neurons impairs the control of the ApoER2/VLDLR-Dab-1-PI3K-PKB-GSK3β axis, leading to pTau. Furthermore, iAβ_1-42 is increased in the EC L-II neurons, possibly due to increased production (via ApoE4-dependent trapping, detailed below), and reduced clearance by impaired mitophagy/autophagy. iAβ_1-42 may bind reelin and thereby reduce levels of signaling competent reelin, in turn impairing PKB mediated inhibition of GSK3β and thus increasing p-Tau. ApoE4 may accentuate this as it tends to get trapped in endosomes along with its lipoprotein receptors, likely mainly ApoER2. This in turn further reduces reelin-signaling, boosting the cascade leading to p-Tau. In concert, ApoE4, trapped in endosomes, increases transcription of APP and thus production of iAβ_1-42, and thereby completes a vicious cycle, whose end product for the affected neurons are NFTs. Furthermore, reduced PKB-activity also inhibits mTOR activity, impacting on mitochondrial homoeostasis and autophagy. Moreover, ApoE4 sequesters ApoER2 in intracellular compartments and reduces the NMDAR phosphorylation in response to reelin in the postsynaptic neuron, leading to impaired neural plasticity. In line with the age onset of AD, age-dependent mitophagy impairment causes accumulation of damaged mitochondria, which further exacerbates AD pathology, including shortage of energy supply, inflammation, oligomerization of iAβ_1-42 and pathological Tau proteins, finally leading to impaired LTP and neuronal plasticity, and neuronal loss. Individuals carrying ApoE4 may have exacerbated mitophagy impairment since ApoE4 inhibits TFEB-dependent regulation of autophagy- and lysosome-related genes. Dashed lines and faint phosphorylation symbols indicate blunted signaling capacity. Abbreviations: Aβ, amyloid-β; AD, Alzheimer’s disease; AMPK, 5′ AMP-activated protein kinase; ApoE, apolipoprotein E; ApoER2, ApoE receptor 2; Ca²⁺, calcium ion; CREB, cAMP response element-binding protein; Dab1, disabled 1; EC, entorhinal cortex; FOXOs, Forkhead box O (FOXO) transcription factors; GSK3β, glycogen synthase kinase 3β; LTP, Long-term potentiation; NMDAR, N-methyl-D-aspartate receptor; PKB, protein kinase B; SIRTs, the NAD⁺-dependent deacetylates sirtuins; SFKs, SRC family tyrosine kinases; ULK1, unc-51 like autophagy activating kinase 1; VLDLR, very-low-density lipoprotein receptor; low-density lipoprotein receptor-related protein 1 (LRP1). Dashed arrows indicate impaired induction/activation.

Figure: Asgeir Kobro-Flatmoen…Evandro F. Fang, Ageing Research Reviews 2021