High‐resolution array‐CGH in patients with oculocutaneous albinism identifies new deletions of the TYR,OCA2, and SLC45A2 genes and a complex rearrangement of the OCA2 gene

Oculocutaneous albinism (OCA) is caused by mutations in six different genes, and their molecular diagnosis encompasses the search for point mutations and intragenic rearrangements. Here, we used high‐resolution array‐comparative genome hybridization (CGH) to search for rearrangements across exons, introns and regulatory sequences of four OCA genes: TYR, OCA2, TYRP1, and SLC45A2. We identified a total of ten new deletions in TYR, OCA2, and SLC45A2. A complex rearrangement of OCA2 was found in two unrelated patients. Whole‐genome sequencing showed deletion of a 184‐kb fragment (identical to a deletion previously found in Polish patients), whereby a large portion of the deleted sequence was re‐inserted after severe reshuffling into intron 1 of OCA2. The high‐resolution array‐CGH presented here is a powerful tool to detect gene rearrangements. Finally, we review all known deletions of the OCA1–4 genes reported so far in the literature and show that deletions or duplications account for 5.6% of all mutations identified in the OCA1–4 genes.     

The albinism of the feral Asinara white donkeys (Equus asinus) is determined by a missense mutation in a highly conserved position of the tyrosinase (TYR) gene deduced protein

A feral donkey population (Equus asinus), living in the Asinara National Park (an island north‐west of Sardinia, Italy), includes a unique white albino donkey subpopulation or colour morph that is a major attraction of this park. Disrupting mutations in the tyrosinase (TYR) gene are known to cause recessive albinisms in humans (oculocutaneous albinism Type 1; OCA1) and other species. In this study, we analysed the donkey TYR gene as a strong candidate to identify the causative mutation of the albinism of these donkeys. The TYR gene was sequenced from 13 donkeys (seven Asinara white albino and six coloured animals). Seven single nucleotide polymorphisms were identified. A missense mutation (c.604C>G; p.His202Asp) in a highly conserved amino acid position (even across kingdoms), which disrupts the first copper‐binding site (CuA) of functional protein, was identified in the homozygous condition (G/G or D/D) in all Asinara white albino donkeys and in the albino son of a trio (the grey parents had genotype C/G or H/D), supporting the recessive mode of inheritance of this mutation. Genotyping 82 donkeys confirmed that Asinara albino donkeys had genotype G/G whereas all other coloured donkeys had genotype C/C or C/G. Across‐population association between the c.604C>G genotypes and the albino coat colour was highly significant (P = 6.17E?18). The identification of the causative mutation of the albinism in the Asinara white donkeys might open new perspectives to study the dynamics of this putative deleterious allele in a feral population and to manage this interesting animal genetic resource.     

A neurodevelopmental disorder with a nonsense mutation in the Ox-2 antigen domain of the amyloid precursor protein (APP) gene

We report a patient, an infant with a neurodevelopmental disorder manifesting intractable complex partial epilepsy, bull's eye maculopathy, microcephaly, bilateral cataracts, truncal hypotonia, and spasticity of all four extremities. Sequencing of genomic DNA revealed mutations in (a) exon 8 (Ox-2 antigen domain) of the amyloid precursor protein (APP) gene: c.1075C>T, p.Arg359^* (b) exon 8 of the senataxin (SETX) gene: c.4738C>T, p.Arg1580Cys, and (c) exon 2 of the ceroid-lipofuscinosis, neuronal 8 (CLN8) gene: c.685C>G, p.Pro229Ala. Using a quantitative method for measurement of various APP-mRNA isoforms, we found that the APP-mRNA isoform of 624 bp with a deletion starting after 49 bp of the 5′ end of exon 3 followed by a complete deletion of exons 4–15, mutations in exon 1: c.22C>T, p.L18F, and exon 3: c.269A>G, p.Q90R encoding APP₂₀₇ isoform was the most abundant one, and would appear to be responsible for the clinical manifestations. This is the first example that may underline the role of the epigenetic regulation in the expression of APP gene leading to a neurodevelopmental disorder resulting from a nonsense mutation in the Ox-2 antigen domain.     

A comparison of the genotoxicity of ethylnitrosourea and ethyl methanesulfonate in lacZ transgenic mice (Muta™Mouse)

We compared the induction of gene mutations and chromosomal aberrations by ethylating agents in lacZ transgenic mice (Muta™Mouse). Chromosomal aberrations were detected by the peripheral blood micronucleus assay. Gene mutations were detected in the lacZ transgene. A small amount of blood was sampled from a tail vessel during the expression time for fixation of gene mutations in vivo; this enabled us to detect and compare clastogenicity and gene mutations in the identical mouse. Single intraperitoneal injections of ENU (50–200 mg/kg) and EMS (100–400 mg/kg) strongly induced micronucleated reticulocytes (MN) detectable in peripheral blood 48 h after treatment. The maximum MN frequencies induced were 6.6% and 3.3% for ENU (100 mg/kg) and EMS (400 mg/kg), respectively (the control value was 0.3%). lacZ mutant frequency (MF) was analyzed in bone marrow and liver 7 days after treatment. Spontaneous MFs were 2.0–4.6x10⁻⁶. MF in bone marrow was increased by ENU to 3.4x10⁻⁵ at 200 mg/kg and induced by EMS to 1.8x10⁻⁵ at 400 mg/kg. In liver, however, both chemicals at their highest doses induced only slight increases in MF. The induction of both micronuclei and lacZ mutations in bone marrow by both ENU and EMS correlated better with O⁶-ethylguanine adducts than with N7-ethylguanine adducts. The mutants (19 for ENU and 12 for EMS) were subjected to DNA sequence analysis. Among EMS-induced mutations, 75% were GC to AT transitions, which were probably caused by O⁶-ethylguanine. Among ENU-induced mutations, in contrast, 40% occurred as AT base pair substitutions (6 AT to TA transversions and 2 AT to GC transitions) (no such mutations were induced by EMS). These results, together with the known reactivity of ENU to thymine suggest that thymine adducts play a significant role in the ENU mutagenesis.     

β‐amino acid substitution to investigate the recognition of angiotensin II (AngII) by angiotensin converting enzyme 2 (ACE2)

In spite of the important role of angiotensin converting enzyme 2 (ACE2) in the cardiovascular system, little is known about the substrate structural requirements of the AngII–ACE2 interaction. Here we investigate how changes in angiotensin II (AngII) structure affect binding and cleavage by ACE2. A series of C3 β‐amino acid AngII analogs were generated and their secondary structure, ACE2 inhibition, and proteolytic stability assessed by circular dichroism (CD), quenched fluorescence substrate (QFS) assay, and LC‐MS analysis, respectively. The β‐amino acid‐substituted AngII analogs showed differences in secondary structure, ACE2 binding and proteolytic stability. In particular, three different subsets of structure‐activity profiles were observed corresponding to substitutions in the N‐terminus, the central region and the C‐terminal region of AngII. The results show that β‐substitution can dramatically alter the structure of AngII and changes in structure correlated with ACE2 inhibition and/or substrate cleavage. β‐amino acid substitution in the N‐terminal region of AngII caused little change in structure or substrate cleavage, while substitution in the central region of AngII lead to increased β‐turn structure and enhanced substrate cleavage. β‐amino acid substitution in the C‐terminal region significantly diminished both secondary structure and proteolytic processing by ACE2. The β‐AngII analogs with enhanced or decreased proteolytic stability have potential application for therapeutic intervention in cardiovascular disease. Copyright © 2010 John Wiley & Sons, Ltd.     

A genome-wide scan study identifies a single nucleotide substitution in ASIP associated with white versus non-white coat-colour variation in sheep (Ovis aries)

In sheep, coat colour (and pattern) is one of the important traits of great biological, economic and social importance. However, the genetics of sheep coat colour has not yet been fully clarified. We conducted a genome-wide association study of sheep coat colours by genotyping 47 303 single-nucleotide polymorphisms (SNPs) in the Finnsheep population in Finland. We identified 35 SNPs associated with all the coat colours studied, which cover genomic regions encompassing three known pigmentation genes (TYRP1, ASIP and MITF) in sheep. Eighteen of these associations were confirmed in further tests between white versus non-white individuals, but none of the 35 associations were significant in the analysis of only non-white colours. Across the tests, the s66432.1 in ASIP showed significant association (P=4.2 × 10⁻¹¹ for all the colours; P=2.3 × 10⁻¹¹ for white versus non-white colours) with the variation in coat colours and strong linkage disequilibrium with other significant variants surrounding the ASIP gene. The signals detected around the ASIP gene were explained by differences in white versus non-white alleles. Further, a genome scan for selection for white coat pigmentation identified a strong and striking selection signal spanning ASIP. Our study identified the main candidate gene for the coat colour variation between white and non-white as ASIP, an autosomal gene that has been directly implicated in the pathway regulating melanogenesis. Together with ASIP, the two other newly identified genes (TYRP1 and MITF) in the Finnsheep, bordering associated SNPs, represent a new resource for enriching sheep coat-colour genetics and breeding.     

A MLCT-switched photochromic copper(II) coordination polymer with 1,2-bis(2′-methyl-5′-(4″-pyridyl)-3′-thienyl)perfluorocyclopentene in crystalline phase

A novel Cu(II) coordination polymer with photochromic 1,2-bis(2′-methyl-5′-(4″-pyridyl)-3′-thienyl)perfluorocyclopentene (BM-4-PTP) was prepared and crystallographically characterized. Its photochromic behavior as well as magnetic property was investigated in crystalline phase. In complex [Cu(BM-4-PTP)Br₂(DMF)₂] (1), each copper atom is bridged by two N atoms of BM-4-PTP, two Br atoms from anions and two O atoms of DMF in an slightly distorted octahedral geometry. The basal planar center is in turn linked by bidentate ligand forming a 1-D polymeric chain. Free ligand showed typical spectral changes upon appropriate optical excitation, indicating the reversible photochromism in crystalline phase. Complex 1 occurred reversible photoisomerization not only through the π-π^∗ transition but also the MLCT transition in crystalline phase. On the other hand, the magnetic property of complex 1 has been investigated by means of ESR. The spectra slightly and reversibly changed in response to UV and visible light supporting the normal photoreactivity in crystalline phase.     

A B2 SINE insertion in the Comt1 gene (Comt1B2i) results in an overexpressing,behavior modifying allele present in classical inbred mouse strains

Catechol‐O‐methyltransferase (COMT) is a key enzyme for dopamine catabolism and COMT is a candidate gene for human psychiatric disorders. In mouse it is located on chromosome 16 in a large genomic region of extremely low variation among the classical inbred strains, with no confirmed single nucleotide polymorphisms (SNPs) between strains C57BL/6J and DBA/2J within a 600‐kB window. We found a B2 SINE in the 3′ untranslated region (UTR) of Comt1 which is present in C57BL/6J (Comt1^B2i) and other strains including 129 (multiple sublines), but is not found in DBA/2J (Comt1⁺) and many other strains including wild‐derived Mus domesticus, M. musculus, M. molossinus, M.castaneus and M. spretus. Comt1^B2i is absent in strains closely related to C57BL/6, such as C57L and C57BR, indicating that it was polymorphic in the cross that gave rise to these strains. The strain distribution of Comt1^B2i indicates a likely origin of the allele in the parental Lathrop stock. A stringent association test, using 670 highly outbred mice (Boulder Heterogeneous Stock), indicates that this insertion allele may be responsible for a difference in behavior related to exploration. Gene expression differences at the mRNA and enzyme activity level (1.7‐fold relative to wild type) indicate a mechanism for this behavioral effect. Taken together, these findings show that Comt1^B2i (a B2 SINE insertion) results in a relatively modest difference in Comt1 expression and enzyme activity (comparable to the human Val‐Met polymorphism) which has a demonstrable behavioral phenotype across a variety of outbred genetic backgrounds.     

腺苷A2a受体在博莱霉素诱导的小鼠肺纤维化中的作用

目的：观察腺苷A_2a受体（A_2aR）在小鼠肺纤维化形成中的调控作用。方法：30只雄性SPF级野生型BALB/C小鼠和20只A_2aR基因敲除BALB/C小鼠,随机分为以下5组：野生型小鼠对照组（A组）、野生型小鼠纤维化组（B组）、A_2aR基因敲除小鼠对照组（C组）、A_2aR基因敲除小鼠纤维化组（D组）、野生型小鼠纤维化+A_2aR激动剂（CGS21680）组（E组）,每组各10只。纤维化组小鼠气管内注入博莱霉素（bleomycin,BLM）溶液50μl （5 mg/kg体重）,对照组在气管内注入等体积生理盐水,注射后立即将小鼠直立旋转3~5 min,使其均匀分布于两肺。A、B、C、D各组每天腹腔注射生理盐水0.5 ml,E组每天腹腔注射A_2aR激动剂（CGS21680）0.5 ml （0.25 mg/kg体重）,连续28 d。第29天取血检测血清转化生长因子β1（TGF-β1）含量;检测肺组织中羟脯氨酸（hydroxyproline,Hyp）、TGF-β1和A_2aR蛋白质含量,TGF-β1 mRNA、A_2aR mRNA的表达,并观察肺组织光镜和超微结构。结果：①光镜和超微结构提示,B组肺泡壁增厚破坏,肺泡腔狭窄或部分陷闭,纤维增生,炎细胞浸润,I型、Ⅱ型肺泡上皮细胞明显空泡化,D组较B组明显,E组表现较B组减轻。Masson染色提示B组、D组小鼠肺组织纤维增生明显,E组明显减少,提示基因缺失加重了小鼠肺纤维化的形成。②与A组比较,B组血清TGF-β1含量,肺组织Hyp含量,TGF-β1、A_2aR蛋白质含量和TGF-β1 mRNA、A_2aR mRNA的表达均明显增高（P<0.01,P<0.05）。与C组比较,D组血清TGF-β1含量、肺组织Hyp、TGF-β1含量和TGF-β1 mRNA表达明显增高（P<0.01,P<0.05）,提示肺纤维化小鼠肺组织Hyp含量增高,TGF-β1表达上调。③与B组相比,D组血清TGF-β1、肺组织Hyp、TGF-β1含量和TGF-β1 mRNA表达明显增高（P<0.01）。与B组比较,E组A_2aR蛋白质含量和A_2aR mRNA的表达均增高（P<0.01）,而血清TGF-β1、肺组织Hyp和TGF-β1蛋白含量及TGF-β1 mRNA表达较B组明显下降（P<0.01,P<0.05）,提示A_2aR基因敲除小鼠肺组织Hyp含量增高、TGF-β1表达上调;A_2aR激动剂可使A_2aR表达上调、TGF-β1表达下降。结论：A_2aR基因敲除小鼠的肺纤维化明显增加。A_2aR在肺纤维化形成中反应性增高,可通过降低TGF-β1的表达而抑制肺纤维化形成。     

A new mutation c.422C>G (p.S141C) in homoand heterozygous forms of the human leptin gene

Mutation g.15409C>G, n.422C>G (p.S141C) in homo-and heterozygous forms of the human LEP gene was identified among some patients of the high mountain village of Karaul, Ashkhabad oblast, Turkmenistan, some of which suffer from obesity. It causes the substitution S120C in the secreted leptin. The mature leptin molecule (146 aa) has only two Cys residues (96C and 146C) forming an S-S bridge, which is important for the hormone function. A third mutation, 120C, in the molecule might disturb the correct formation of the S-S bond and could alter the leptin activity.     

Aneuploidy in metaphases II of spermatocytes of wild house mice from a hybrid zone between a Robertsonian population (CD: 2n = 22) and a population with the standard karyotype (2n = 40)

Meiotic metaphases II from archival slides were studied of male house mice caught in a hybrid zone between a population monomorphic for nine centric fusions (2n = 22) and a population with the standard karyotype (2n = 40), near Rome. The frequency of aneuploidy increases, up to 50%, with increasing number of heterozygous centric fusions (1–4). This revised version was published online in July 2006 with corrections to the Cover Date.     

Further evidence supporting an inner sphere mechanism in the NO reduction of the copper(II) complex Cu(dmp)2 (dmp = 2,9-dimethyl-1,10-phenanthroline)

Described are further studies directed towards elucidating the mechanism of the nitric oxide reduction of the copper(II) model system, Cu(dmp)2(2+) (I, dmp=2,9-dimethyl-1,10-phenanthroline). The reaction of I with NO in methanol results in the formation of Cu(dmp)2+ (II) and methyl nitrite (CH3ONO), with a second order rate constant kNO=38.1 M-1 s-1 (298K). The activation parameters for this reaction in buffered aqueous medium were measured to be DeltaH(double dagger)=41.6 kJ/mol and DeltaS(double dagger)=-82.7 kJ/mol deg. The addition of azide ion (N3-) as a competing nucleophile results in a marked acceleration in the rate of the copper(II) reduction. Analysis of the kinetics for the NO reduction of the bulkier Cu(dpp)(2)2+ (IV, dpp=2,9-diphenyl-1,10-phenanthroline) and the stronger oxidant, Cu(NO2-dmp)2(2+) (V, NO2-dmp=5-nitro-2,9-dimethyl-1,10-phenanthroline), gave the second order rate constants kNO=21.2 and 29.3 M-1 s-1, respectively. These results argue against an outer sphere electron transfer pathway and support a mechanism where the first step involves the formation of a copper-nitrosyl (Cu(II)-NO or Cu(I)-NO+) adduct. This would be followed by the nucleophilic attack on the bound NO and the labilization of RONO to form the nitrite products and the cuprous complex.     

A transgene carrying an A2G missense mutation in the SMN gene modulates phenotypic severity in mice with severe (type I) spinal muscular atrophy

5q spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans and the leading genetic cause of infantile death. Patients lack a functional survival of motor neurons (SMN1) gene, but carry one or more copies of the highly homologous SMN2 gene. A homozygous knockout of the single murine Smn gene is embryonic lethal. Here we report that in the absence of the SMN2 gene, a mutant SMN A2G transgene is unable to rescue the embryonic lethality. In its presence, the A2G transgene delays the onset of motor neuron loss, resulting in mice with mild SMA. We suggest that only in the presence of low levels of full-length SMN is the A2G transgene able to form partially functional higher order SMN complexes essential for its functions. Mild SMA mice exhibit motor neuron degeneration, muscle atrophy, and abnormal EMGs. Animals homozygous for the mutant transgene are less severely affected than heterozygotes. This demonstrates the importance of SMN levels in SMA even if the protein is expressed from a mutant allele. Our mild SMA mice will be useful in (a) determining the effect of missense mutations in vivo and in motor neurons and (b) testing potential therapies in SMA.     

Investigation of the MSO4 · xH2O (M = Zn, x = 7; M = Cd, x = 8/3)/methyl 2-pyridyl ketone oxime reaction system: A novel Cd(II) coordination polymer versus mononuclear and dinuclear Zn(II) complexes

The reactions of methyl 2-pyridyl ketone oxime, (py)C(Me)NOH, with MSO₄ · xH₂O (M = Zn, x = 7; M = Cd, x = 8/3), in the absence of an external base, have been investigated. The synthetic study has led to the two new complexes [Zn(SO₄){(py)C(Me)NOH}(H₂O)₃] · H₂O (1 · H₂O) and [Zn₂(SO₄)₂{(py)C(Me)NOH}₄] · (py)C(Me)NOH [2 · (py)C(Me)NOH], and the coordination polymer [Cd(SO₄){(py)C(Me)NOH}(H₂O)]_n · [Cd(SO₄){(py)C(Me)NOH}(H₂O)₂]_n (3). In the three complexes the organic ligand chelates through its nitrogen atoms. The sulfate anion in 1 · H₂O is monodentate; the complex molecule is the mer isomer considering the positions of the aqua ligands. The Zn^II centers in 2 · (py)C(Me)NOH are bridged by two syn, anti η¹:η¹:μ₂ ligands; each metal ion has the cis-cis-trans disposition of the coordinated sulfate oxygen, pyridyl nitrogen and oxime nitrogens, respectively. The molecular structure of 3 is unique consisting of two different linear and ladder - type chains. π-π stacking interactions and/or hydrogen bonds lead to the formation of interesting supramolecular architectures in the three complexes. The thermal decomposition of complex 3 has been studied. Characteristic vibrational (IR, Raman) bands are discussed in terms of the nature of bonding and the structures of the three complexes.     

Hyposensitivity to the amnesic effects of scopolamine or amyloid β25–35 peptide in heterozygous acetylcholinesterase knockout (AChE) mice

We examined the sensitivity of AChE^+/− mice to the amnesic effects of scopolamine and amyloid β peptide. AChE^+/− and AChE^+/+ littermates, tested at 5–9 weeks of age, failed to show any difference in locomotion, exploration and anxiety in the open-field test, or in-place learning in the water-maze. However, when treated with the muscarinic receptor antagonist scopolamine (0.5, 5 mg/kg s.c.) 20 min before each water-maze training session, learning impairments were observed at both doses in AChE^+/+ mice, but only at the highest dose in AChE^+/− mice. The central injection of Aβ_25–35 peptide (9 nmol) induced learning deficits only in AChE^+/+ but not in AChE^+/− mice. Therefore, the hyper-activity of cholinergic systems in AChE^+/− mice did not result in increased memory abilities, but prevented the deleterious effects of muscarinic blockade or amyloid toxicity.     

The effect of carbamazepine on bone structure and strength in control and osteogenesis imperfecta (Col1a2 +/p.G610C ) mice

The inherited brittle bone disease osteogenesis imperfecta (OI) is commonly caused by COL1A1 and COL1A2 mutations that disrupt the collagen I triple helix. This causes intracellular endoplasmic reticulum (ER) retention of the misfolded collagen and can result in a pathological ER stress response. A therapeutic approach to reduce this toxic mutant load could be to stimulate mutant collagen degradation by manipulating autophagy and/or ER‐associated degradation. Since carbamazepine (CBZ) both stimulates autophagy of misfolded collagen X and improves skeletal pathology in a metaphyseal chondrodysplasia model, we tested the effect of CBZ on bone structure and strength in 3‐week‐old male OI Col1a2 ^+/p.G610C and control mice. Treatment for 3 or 6 weeks with CBZ, at the dose effective in metaphyseal chondrodysplasia, provided no therapeutic benefit to Col1a2 ^+/p.G610C mouse bone structure, strength or composition, measured by micro‐computed tomography, three point bending tests and Fourier‐transform infrared microspectroscopy. In control mice, however, CBZ treatment for 6 weeks impaired femur growth and led to lower femoral cortical and trabecular bone mass. These data, showing the negative impact of CBZ treatment on the developing mouse bones, raise important issues which must be considered in any human clinical applications of CBZ in growing individuals.     

A novel c.1037C > G (p.Ala346Gly) mutation in TP63 as cause of the ectrodactyly-ectodermal dysplasia and cleft lip/palate (EEC) syndrome

Ectrodactyly – ectodermal dysplasia and cleft lip/palate (EEC) syndrome (OMIM 604292) is a rare disorder determined by mutations in the TP63 gene. Most cases of EEC syndrome are associated to mutations in the DNA binding domain (DBD) region of the p63 protein. Here we report on a three-generation Brazilian family with three individuals (mother, son and grandfather) affected by EEC syndrome, determined by a novel mutation c.1037C > G (p.Ala346Gly). The disorder in this family exhibits a broad spectrum of phenotypes: two individuals were personally examined, one presenting the complete constellation of EEC syndrome manifestations and the other presenting an intermediate phenotype; the third affected, a deceased individual not examined personally and referred to by his daughter, exhibited only the split-hand/foot malformation (SHFM). Our findings contribute to elucidate the complex phenotype-genotype correlations in EEC syndrome and other related TP63-mutation syndromes. The possibility of the mutation c.1037C > G being related both to acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome and SHFM is also raised by the findings here reported.     

Nurr1 (NR4A2) regulates Alzheimer’s disease‐related pathogenesis and cognitive function in the 5XFAD mouse model

The orphan nuclear receptor Nurr1 (also known as NR4A2) is critical for the development and maintenance of midbrain dopaminergic neurons, and is associated with Parkinson's disease. However, an association between Nurr1 and Alzheimer's disease (AD)‐related pathology has not previously been reported. Here, we provide evidence that Nurr1 is expressed in a neuron‐specific manner in AD‐related brain regions; specifically, it is selectively expressed in glutamatergic neurons in the subiculum and the cortex of both normal and AD brains. Based on Nurr1’s expression patterns, we investigated potential functional roles of Nurr1 in AD pathology. Nurr1 expression was examined in the hippocampus and cortex of AD mouse model and postmortem human AD subjects. In addition, we performed both gain‐of‐function and loss‐of‐function studies of Nurr1 and its pharmacological activation in 5XFAD mice. We found that knockdown of Nurr1 significantly aggravated AD pathology while its overexpression alleviated it, including effects on Aβ accumulation, neuroinflammation, and neurodegeneration. Importantly, 5XFAD mice treated with amodiaquine, a highly selective synthetic Nurr1 agonist, showed robust reduction in typical AD features including deposition of Aβ plaques, neuronal loss, microgliosis, and impairment of adult hippocampal neurogenesis, leading to significant improvement of cognitive impairment. These in vivo and in vitro findings suggest that Nurr1 critically regulates AD‐related pathophysiology and identify Nurr1 as a novel AD therapeutic target.