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The microstructural characteristics of white and gray matter in mild cognitive impairment (MCI) and the early-stage of Alzheimer's disease (AD) remain unclear. This study aimed to systematically identify the microstructural damages of MCI/AD in studies using neurite orientation dispersion and density imaging (NODDI), and explore their correlations with cognitive performance. Multiple databases were searched for eligible studies. The 10 eligible NODDI studies were finally included. Patients with MCI/AD showed overall significant reductions in neurite density index (NDI) of specific white matter structures in bilateral hemispheres (left hemisphere: -0.40 [-0.53, -0.27], P < 0.001; right: -0.33 [-0.47, -0.19], P < 0.001), involving the bilateral superior longitudinal fasciculus (SLF), uncinate fasciculus (UF), the left posterior thalamic radiation (PTR), and the left cingulum. White matter regions exhibited significant increased orientation dispersion index (ODI) (left: 0.25 [0.02, 0.48], P < 0.05; right: 0.27 [0.07, 0.46], P < 0.05), including the left cingulum, the right UF, and the bilateral parahippocampal cingulum (PHC), and PTR. Additionally, the ODI of gray matter showed significant reduction in bilateral hippocampi (left: -0.97 [-1.42, -0.51], P < 0.001; right: -0.90 [-1.35, -0.45], P < 0.001). The cognitive performance in MCI/AD was significantly associated with NDI (r = 0.50, P < 0.001). Our findings highlight the microstructural changes in MCI/AD were characterized by decreased fiber orientation dispersion in the hippocampus, and decreased neurite density and increased fiber orientation dispersion in specific white matter tracts, including the cingulum, UF, and PTR. Moreover, the decreased NDI may indicate the declined cognitive level of MCI/AD patients. [ABSTRACT FROM AUTHOR]

Differential gene expression (DGE) analysis has been widely employed to identify genes expressed differentially with respect to a trait of interest using RNA sequencing (RNA-Seq) data. Recent RNA-Seq data with large samples pose challenges to existing DGE methods, which were mainly developed for dichotomous traits and small sample sizes. Especially, existing DGE methods are likely to result in inflated false positive rates. To address this gap, we employed a linear mixed model (LMM) that has been widely used in genetic association studies for DGE analysis of quantitative traits. We first applied the LMM method to the discovery RNA-Seq data of dorsolateral prefrontal cortex (DLPFC) tissue (n = 632) with four continuous measures of Alzheimer's Disease (AD) cognitive and neuropathologic traits. The quantile–quantile plots of p-values showed that false positive rates were well calibrated by LMM, whereas other methods not accounting for sample-specific mixed effects led to serious inflation. LMM identified 37 potentially significant genes with differential expression in DLPFC for at least one of the AD traits, 17 of which were replicated in the additional RNA-Seq data of DLPFC, supplemental motor area, spinal cord, and muscle tissues. This application study showed not only well calibrated DGE results by LMM, but also possibly shared gene regulatory mechanisms of AD traits across different relevant tissues. [ABSTRACT FROM AUTHOR]

Muscarinic acetylcholine receptors (mAChRs) respond to the neurotransmitter acetylcholine and play important roles in human nervous system. Muscarinic receptor 4 (M4R) is a promising drug target for treating neurological and mental disorders, such as Alzheimer's disease and schizophrenia. However, the lack of understanding on M4R's activation by subtype selective agonists hinders its therapeutic applications. Here, we report the structural characterization of M4R selective allosteric agonist, compound-110, as well as agonist iperoxo and positive allosteric modulator LY2119620. Our cryo-electron microscopy structures of compound-110, iperoxo or iperoxo-LY2119620 bound M4R-Gi complex reveal their different interaction modes and activation mechanisms of M4R, and the M4R-ip-LY-Gi structure validates the cooperativity between iperoxo and LY2119620 on M4R. Through the comparative structural and pharmacological analysis, compound-110 mostly occupies the allosteric binding pocket with vertical binding pose. Such a binding and activation mode facilitates its allostersic selectivity and agonist profile. In addition, in our schizophrenia-mimic mouse model study, compound-110 shows antipsychotic activity with low extrapyramidal side effects. Thus, this study provides structural insights to develop next-generation antipsychotic drugs selectively targeting on mAChRs subtypes. The authors report the structural characterization of M4R selective allosteric agonist, compound-110, as well as agonist iperoxo and positive allosteric modulator LY2119620. The cryo-EM structures of compound-110, iperoxo or iperoxo-LY2119620 bound M4R-Gi complex reveal different interaction modes and activation mechanisms of M4R. An antipsychotic activity of compound-110 with low extrapyramidal side effects in a schizophrenia-mimic mouse model is also reported. Thus, the study provides structural insights for selectively targeting mAChRs subtypes. [ABSTRACT FROM AUTHOR]

Aluminum is a widespread environmental neurotoxicant that can induce Alzheimer's disease (AD)-like damage, such as neuronal injury and impairment of learning and memory. Several studies have shown that aluminum could reduce the synaptic plasticity, but its molecular mechanism remains unclear. In this study, rats were treated with aluminum maltol (Al(mal)3) to establish a toxic animal model and PMA was used to interfere with the expression of PKC. The Morris water maze and open field test were used to investigate the behavioral changes of the rats. Western blotting and RT-PCR were used to detect the expression levels of NMDAR subunits, PKC and CaMKII. The results showed that Al(mal)3 damaged learning and memory function and reduced anxiety in rats. During this process, the expression of PKC was downregulated and it inhibited the expression of NMDARs through the phosphorylation of CaMKII. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized by amyloid plaques and progressive cerebral atrophy. Here, we report FAM222A as a putative brain atrophy susceptibility gene. Our cross-phenotype association analysis of imaging genetics indicates a potential link between FAM222A and AD-related regional brain atrophy. The protein encoded by FAM222A is predominantly expressed in the CNS and is increased in brains of patients with AD and in an AD mouse model. It accumulates within amyloid deposits, physically interacts with amyloid-β (Aβ) via its N-terminal Aβ binding domain, and facilitates Aβ aggregation. Intracerebroventricular infusion or forced expression of this protein exacerbates neuroinflammation and cognitive dysfunction in an AD mouse model whereas ablation of this protein suppresses the formation of amyloid deposits, neuroinflammation and cognitive deficits in the AD mouse model. Our data support the pathological relevance of protein encoded by FAM222A in AD. In this study the authors identify a possible link between the gene FAM222A and brain atrophy. The protein it encodes is found to accumulate in plaques seen in Alzheimer's disease, and functional analysis suggests it interacts with amyloid-beta. [ABSTRACT FROM AUTHOR]

Though sleep disturbance constitutes the risk factor for Alzheimer's disease (AD), the underlying mechanism is still unclear. This study aims to explore the interaction between sleep disturbances and AD on brain function. We included 192 normal controls, 111 mild cognitive impairment (MCI), and 30 AD patients, with either poor or normal sleep (PS, NS, respectively). To explore the strength and stability of brain activity, we used static amplitude of low-frequency fluctuation (sALFF) and dynamic ALFF (dALFF) variance. Further, we examined white matter hyperintensities (WMH) and amyloid PET deposition, representing the vascular risk factor and AD-related hallmark, respectively. We observed that sleep disturbance significantly interacted with disease severity, exposing distinct effects on sALFF and dALFF variance. Interestingly, PS groups showed the dALFF variance trajectory of initially increased, then decreased and finally increased along the AD spectrum, while showing the opposite trajectory of sALFF. Further correlation analysis showed that the WMH burden correlates with dALFF variance in PS groups. Conclusively, our study suggested that sleep disturbance interacts with AD severity, expressing as effects of compensatory in MCI and de-compensatory in AD, respectively. Further, vascular impairment might act as important pathogenesis underlying the interaction effect between sleep and AD. [ABSTRACT FROM AUTHOR]

The major function of microtubule-associated protein tau is to promote microtubule assembly in the central nervous system. However, aggregation of abnormally phosphorylated tau is a hallmark of tauopathies. Although the molecular mechanisms of conformational transitions and assembling of tau molecules into amyloid fibril remain largely unknown, several factors have been shown to promote tau aggregation, including mutations, polyanions, phosphorylation, and interactions with other proteins. 14-3-3 proteins are a family of highly conserved, multifunctional proteins that are mainly expressed in the central nervous system. Being a scaffolding protein, 14-3-3 proteins interact with tau and regulate tau phosphorylation by bridging tau with various protein kinases. 14-3-3 proteins also directly regulate tau aggregation via specific and non-specific interactions with tau. In this review, we summarize recent advances in characterization of tau conformation and tau/14-3-3 interaction. We discuss the connection between 14-3-3 binding and tau aggregation with a special emphasis on the regulatory role of 14-3-3 on tau conformation. [ABSTRACT FROM AUTHOR]

This image incorrectly showed the same sample as shown in the original Figure 4g, top row (A 1-42), under "0.5h". In the original version of the manuscript, the image shown in Figure 4g, bottom row (A 1-42 + rAggregatin), under "6h" was incorrect. [Extracted from the article]

Objective: Decline, disruption, or alterations of nicotinic cholinergic mechanisms contribute to cognitive dysfunctions like Alzheimer's disease (AD). Although amyloid-β (Aβ) aggregation is a pathological hallmark of AD, the mechanisms by which Aβ peptides modulate cholinergic synaptic transmission and memory loss remain obscure. This study was aimed to investigate the potential synaptic modulation by Aβ of the cholinergic synapses between olfactory receptor neurons and projection neurons (PNs) in the olfactory lobe of the fruit fly. Methods: Cholinergic spontaneous and miniature excitatory postsynaptic current (mEPSC) were recorded with whole-cell patch clamp from PNs in Drosophila AD models expressing Aβ40, Aβ42, or Aβ42Arc peptides in neural tissue. Results: In fly pupae (2 days before eclosion), overexpression of Aβ42 or Aβ42Arc, but not Aβ40, led to a significant decrease of mEPSC frequency, while overexpression of Aβ40, Aβ42, or Aβ42Arc had no significant effect on mEPSC amplitude. In contrast, Pavlovian olfactory associative learning and lifespan assays showed that both short-term memory and lifespan were decreased in the Drosophila models expressing Aβ40, Aβ42, or Aβ42Arc. Conclusion: Both electrophysiological and behavioral results showed an effect of Aβ peptide on cholinergic synaptic transmission and suggest a possible mechanism by which Aβ peptides cause cholinergic neuron degeneration and the consequent memory loss. [ABSTRACT FROM AUTHOR]