Re-emphasizing early Alzheimer’s disease pathology starting in select entorhinal neurons,with a special focus on mitophagy

The entorhinal-hippocampal system contains distinct networks subserving declarative memory. This system is selectively vulnerable to changes of ageing and pathological processes. The entorhinal cortex (EC) is a pivotal component of this memory system since it serves as the interface between the neocortex and the hippocampus. EC is heavily affected by the proteinopathies of Alzheimer’s disease (AD). These appear in a stereotypical spatiotemporal manner and include increased levels of intracellular amyloid-beta Aβ (iAβ), parenchymal deposition of Aβ plaques, and neurofibrillary tangles (NFTs) containing abnormally processed Tau. Increased levels of iAβ and the formation of NFTs are seen very early on in a population of neurons belonging to EC layer II (EC LII), and recent evidence leads us to believe that this population is made up of highly energy-demanding reelin-positive (RE+) projection neurons. Mitochondria are fundamental to the energy supply, metabolism, and plasticity of neurons. Evidence from AD postmortem brain tissues supports the notion that mitochondrial dysfunction is one of the initial pathological events in AD, and this is likely to take place in the vulnerable RE + EC LII neurons. Here we review and discuss these notions, anchored to the anatomy of AD, and formulate a hypothesis attempting to explain the vulnerability of RE + EC LII neurons to the formation of NFTs. We attempt to link impaired mitochondrial clearance to iAβ and signaling involving both apolipoprotein 4 and reelin, and argue for their relevance to the formation of NFTs specifically in RE + EC LII neurons during the prodromal stages of AD. We believe future studies on these interactions holds promise to advance our understanding of AD etiology and provide new ideas for drug development.     

Reelin inhibits migration of sympathetic preganglionic neurons in the spinal cord of the chick

The present study examined the effects of Reelin in the migration of sympathetic preganglionic neurons (SPN) in the spinal cord of the chick. SPN in the chick first migrate from the neuroepithelium to the ventrolateral spinal cord. They then undergo a secondary migration to cluster adjacent to the central canal, forming the column of Terni (CT). During secondary migration, abundant Reelin is found in large areas of the ventral spinal cord; the only areas devoid of Reelin are areas occupied by SPN or somatic motor neurons and the pathway along which SPN migrate. Ectopic expression of Reelin in the pathway of SPN through electroporation of full-length Reelin DNA stopped SPN migration toward their destination. The spatiotemporal pattern of Reelin expression, along with the inhibition of SPN migration by exogenous Reelin, suggests that Reelin functions as a barrier to SPN migration during normal development of the spinal cord.     

Transient and compartmental expression of the reeler gene product Reelin in the developing rat striatum

Mammalian neostriatum is composed of two neurochemically and neuroanatomically defined compartments, called the patches and matrix. The present study concerns a search for neurochemical molecules involved in formation of the striatal compartments. Using the monoclonal antibody CR-50, we here disclose a transient expression of the reeler gene product Reelin, which is known to play a crucial role in neuronal positioning and axon guidance during corticogenesis, in the developing striatum of rats. Furthermore, Reelin protein is differentially concentrated in the two distinct compartments showing a mosaic-like fashion in the early postnatal period: the compartments of heightened CR-50-immunolabeling correspond to so-called “dopamine islands” (i.e., developing striosomes) visualized by tyrosine hydroxylase (TH)-immunostaining. On the basis of these findings, we hypothesize that Reelin protein may play a role in developmental organization of the striatal compartments.     

The inverted neurogenetic gradient of the mammalian isocortex: development and evolution

In this paper we review recent evidence on the molecular control of cell migration in the isocortex, and present an hypothesis for the evolutionary origin of the inside-out neurogenetic gradient of this structure. We suggest that there are at least two key factors involved in the acquisition of the inside-out gradient: (i) the expression of the protein reelin, which arrests the migration of cortical plate cells by detaching them from the radial glial fiber. This permits younger neurons to use the same fiber to migrate past the previous neurons; and (ii) the second factor is an intracellular signaling pathway dependent on a cyclin-dependent protein kinase (Cdk5). Cdk5 may work by inhibiting N-cadherin mediated cell aggregation as young cells cross the cortical plate, permitting them to move to the more superficial layers. Interestingly, the mutation in Cdk5 affects the migration of only those cells belonging to superficial layers, which are considered to be an evolutionary acquisition of the mammalian isocortex.     

精神分裂症患者外周血液中Reelin蛋白的表达

目的探讨Reelin蛋白与精神分裂症的关系。方法将89例精神分裂症患者作为精神分裂症组,89例健康者作为对照组,采用Western blot检测其外周血Reelin蛋白的表达。结果精神分裂症组患者外周血Reelin蛋白表达水平（0.66±0.27）显著低于对照组（1.01±0.23）（P〈0.05）。精神分裂症组男、女性患者Reelin蛋白表达水平分别为0.66±0.22、0.66±0.26,二者差异无统计学意义（t=0.181,P〉0.05）,对照组男、女性受检者Reelin蛋白表达水平分别为1.01±0.25、1.02±0.26,二者差异无统计学意义（t=0.201,P〉0.05）。结论 Reelin蛋白表达的降低与精神分裂症有关。     

Blood reelin in the progression of chronic liver disease

PurposeReelin is an extracellular matrix protein originally found to be associated with neuropsychiatric disorders. Recent findings indicate, that reelin may also play an important role in the process of liver fibrosis as well as in the development of hepatocellular carcinoma (HCC). Against this background, the aim of our study was to explore alterations in blood reelin levels in different stages of chronic liver diseases.Patients and methodsWe analyzed blood samples of patients with chronic liver disease without liver fibrosis (n ​= ​25), with liver fibrosis (n ​= ​36), with liver cirrhosis (n ​= ​74), with HCC (n ​= ​26) as well as of healthy controls (n ​= ​15). Blood reelin concentrations were determined utilizing an enzyme-linked immunosorbent assay.ResultsBlood reelin levels were significantly elevated in patients who had liver fibrosis or cirrhosis compared to patients without liver fibrosis and healthy controls (13.9 (10.2–21.1) ng/ml vs. 11.2 (8.8–16.8) ng/ml, p ​= ​0.032). Importantly, patients with HCC displayed significantly higher reelin concentrations compared to patients with liver cirrhosis alone (27.0 (17.3–35.9) ng/ml vs. 16.6 (11.0–22.7) ng/ml, p ​< ​0.001). Blood reelin was not relevantly linked to liver function, inflammation and etiology of liver disease.ConclusionsOur results demonstrate, that blood reelin levels are altered in different stages of chronic liver disease, which makes reelin a potential biomarker in this setting. This may be especially relevant with regard to its use as an additional tumor marker of HCC.     

Migration of sympathetic preganglionic neurons in the spinal cord of a C3G‐deficient mouse suggests that C3G acts in the reelin signaling pathway

Proper positioning of sympathetic preganglionic neurons (SPNs) in the spinal cord is regulated by reelin signaling. SPNs in reeler (which lacks reelin), and in mice deficient in components of the reelin signaling pathway (reelin receptors VldlR and ApoER2, the cytoplasmic adaptor protein Dab1, Src and Fyn of the Src‐family of non‐receptor protein tyrosine kinases, and CrkL) are located adjacent to the central canal instead of in the intermediolateral column (IML) of the spinal cord. Events downstream of CrkL in control of SPN migration are unclear. The present study asks whether Rap guanine nucleotide exchange factor (GEF) 1 (C3G/Rapgef1), a Ras family GEF that binds CrkL, could act downstream in the reelin signaling pathway in control of SPN migration. SPN migration was examined in a hypopmorphic C3G mutant mouse (C3G^gt/gt) by using retrograde DiI labeling and NOS immunostaining. The results showed that SPN in the C3G^gt/gt mutant migrate abnormally toward the central canal as in reeler. However, unlike reeler, levels of reelin in the C3G^gt/gt spinal cord are normal, and Dab1 immunostaining is undetectable. These results provide genetic evidence that C3G regulates SPN migration, and suggest that C3G acts downstream in the reelin signaling pathway in control of SPN migration. J. Comp. Neurol., 520:3194–3202, 2012. © 2012 Wiley Periodicals, Inc.     

Reelin调节小鼠喙端迁移流发育的形态学观察

目的 探讨小鼠室管膜下区（SVZ）的神经干细胞孵育成熟以及沿喙端迁移流（RMS）切线迁移至嗅球(OB)的过程,尤其是Reelin对细胞迁移和细胞分化的影响。方法 选用野生型（WT）小鼠50只和纯合reeler小鼠23只胚胎16 d至生后90 d的各年龄点小鼠大脑,应用尼氏染色、免疫荧光染色、墨汁灌注及电子显微镜技术标记并观察小鼠大脑的神经干细胞、胶质细胞以及血管发生之间的相互关系,比较两组小鼠RMS的发育情况。结果 胚胎后期至出生早期,在SVZ分布着大量的胶质细胞、神经干细胞和血管网,它们相互联系构成SVZ神经干细胞孵育的血管龛(niche);神经干细胞在niche中孵育成熟后可以进入RMS,切线迁移至嗅球,到达嗅球后转变为放射状迁移,分化为各种神经元整合入嗅球;神经干细胞在RMS的迁移过程中,放射状胶质细胞协同血管为其提供支架引导;reeler小鼠也能形成RMS,但形态有所改变,主要在嗅球处,神经干细胞失去规律排列,呈散乱分布。结论 室管膜下区的niche是神经干细胞的主要来源;血管协同放射状胶质细胞为RMS中的神经干细胞提供支架引导作用;作为调节细胞迁移的重要信号,Reelin可以通过其交互作用影响血管的发育,Reelin缺失导致嗅球处神经干细胞放射状迁移的转变障碍。     

Reelin Regulates Neuronal Excitability through Striatal-Enriched Protein Tyrosine Phosphatase (STEP61) and Calcium Permeable AMPARs in an NMDAR-Dependent Manner

Alzheimer''s disease (AD) is a progressive neurodegenerative disease marked by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles. Aβ oligomers cause synaptic dysfunction early in AD by enhancing long-term depression (LTD; a paradigm for forgetfulness) via metabotropic glutamate receptor (mGluR)-dependent regulation of striatal-enriched tyrosine phosphatase (STEP₆₁). Reelin is a neuromodulator that signals through ApoE (apolipoprotein E) receptors to protect the synapse against Aβ toxicity (Durakoglugil et al., 2009) Reelin signaling is impaired by ApoE4, the most important genetic risk factor for AD, and Aβ-oligomers activate metabotropic glutamate receptors (Renner et al., 2010). We therefore asked whether Reelin might also affect mGluR-LTD. To this end, we induced chemical mGluR-LTD using DHPG (Dihydroxyphenylglycine), a selective mGluR5 agonist. We found that exogenous Reelin reduces the DHPG-induced increase in STEP₆₁, prevents the dephosphorylation of GluA2, and concomitantly blocks mGluR-mediated LTD. By contrast, Reelin deficiency increased expression of Ca²⁺-permeable GluA2-lacking AMPA receptors along with higher STEP₆₁ levels, resulting in occlusion of DHPG-induced LTD in hippocampal CA1 neurons. We propose a model in which Reelin modulates local protein synthesis as well as AMPA receptor subunit composition through modulation of mGluR-mediated signaling with implications for memory consolidation or neurodegeneration.SIGNIFICANCE STATEMENT Reelin is an important neuromodulator, which in the adult brain controls synaptic plasticity and protects against neurodegeneration. Amyloid-β has been shown to use mGluRs to induce synaptic depression through endocytosis of NMDA and AMPA receptors, a mechanism referred to as LTD, a paradigm of forgetfulness. Our results show that Reelin regulates the phosphatase STEP, which plays an important role in neurodegeneration, as well as the expression of calcium-permeable AMPA receptors, which play a role in memory formation. These data suggest that Reelin uses mGluR LTD pathways to regulate memory formation as well as neurodegeneration.     

Role for Reelin-induced cofilin phosphorylation in the assembly of sympathetic preganglionic neurons in the murine intermediolateral column

Sympathetic preganglionic neurons (SPNs) are located in the intermediolateral column (IMLC) of the spinal cord. This specific localization results from primary and secondary migratory processes during spinal cord development. Thus, following neurogenesis in the neuroepithelium, SPNs migrate first in a ventrolateral direction and then, in a secondary step, dorsolaterally to reach the IMLC. These migratory processes are controlled, at least in part, by the glycoprotein Reelin, which is known to be important for the development of laminated brain structures. In reeler mutants deficient in Reelin, SPNs initially migrate ventrolaterally as normal. However, most of them then migrate medially to become eventually located near the central canal. Here, we provide evidence that in wild-type animals this aberrant medial migration towards the central canal is prevented by Reelin-induced cytoskeletal stabilization, brought about by phosphorylation of cofilin. Cofilin plays an important role in actin depolymerization, a process required for the changes in cell shape during migration. Phosphorylation of cofilin renders it unable to depolymerize F-actin, thereby stabilizing the cytoskeleton. Using immunostaining for phosphorylated cofilin (p-cofilin), we demonstrate that SPNs in wild-type animals, but not in reeler mutants and other mutants of the Reelin signalling cascade, are immunoreactive for p-cofilin. These findings suggest that Reelin near the central canal induces cofilin phosphorylation in SPNs, thereby preventing them from aberrant migration towards the central canal. The results extend our previous studies on cortical neurons in which Reelin in the marginal zone was found to stabilize the leading processes of migrating neurons and terminate the migration process.