The protective innate immune response of β-amyloid peptide (Aβ) has been indicated as a risk factor for Alzheimer\'s disease (AD) due to the rapid amyloidosis. In order to obtain molecular-level insights into the protective and pathogenic roles of Aβ, the binding modes between Aβ1-42 and the envelop glycoprotein D (gD) of Herpes simplex virus-1 (HSV-1)/Aβ1-42 were theoretically investigated by using molecular docking, molecular dynamics (MD) simulations and binding free energy decomposition methods in the present study. The Aβ1-42 stably binds to the envelop gD via intermolecular hydrogen bonds and van der Waals (vdW) interactions. The Aβ1-42 acquires its equilibrium with higher fluctuation amplitude and a better structured C-terminal in the HSV-1 gD-Aβ1-42 complex comparing to that in the Aβ1-42-Aβ1-42 complex. The amino acid residues of Aβ1-42 involved in the formation of the Aβ1-42 dimer are fully free and accessible in the HSV-1 gD-Aβ1-42 complex. It is favorable for the Aβ1-42 monomer to interact with the HSV-1 gD-Aβ1-42 complex. It may be responsible for the rapid amyloidosis which entraps the herpesvirus as well as causing AD.

Growing evidence has suggested the poor correlation between brain amyloid plaque and Alzheimer\'s disease (AD). Presenilin1 (PS1) and presenilin2 (PS2) conditional double knockout (cDKO) mice exhibited the reduced 42-amino acid amyloid-β peptide (Aβ1-42) level and AD-like symptoms, indicating a different pathological mechanism from the amyloid cascade hypothesis for AD. Here we found that exogenous synthetic Aβ1-42 monomers could improve the impaired memory not only in cDKO mice without Aβ1-42 deposition but also in the APP/PS1/Tau triple transgenic 3 × Tg-AD mice with Aβ1-42 deposition, which were mediated by α7-nAChR. Our findings demonstrate for the first time that reduced soluble Aβ1-42 level is the main cause of cognitive dysfunction in cDKO mice, and support the opinions that low soluble Aβ1-42 level due to Aβ1-42 deposition may also cause cognitive deficits in 3 × Tg-AD mice. Therefore, \"loss-of-function\" of Aβ1-42 should be avoided when designing therapies aimed at reducing Aβ1-42 burden in AD.

BACKGROUND: The importance of aromaticity vs. hydrophobicity of the central hydrophobic core (CHC, residues 17-20) in governing fibril formation in Aβ(1-42) has been the focus of an ongoing debate in the literature.
BACKGROUND: Mutations in the CHC (especially at Phe19 and Phe20) have been used to examine the relative impact of hydrophobicity and aromaticity on the degree of aggregation of Aβ(1-42). However, the results have not been conclusive.
METHODS: Partial least squares (PLS) modeling of aggregation rates, using reduced properties of a series of position 19 mutants, was employed to identify the physicochemical properties that had the greatest impact on the extent of aggregation.
RESULTS: The PLS models indicate that hydrophobicity at position 19 of Aβ(1-42) appears to be the primary and dominant factor in controlling Aβ(1-42) aggregation, with aromaticity having little effect.
CONCLUSIONS: This study illustrates the value of using reduced properties of amino acids in conjunction with PLS modeling to investigate mutational effects in peptides and proteins, as the reduced properties can capture in a quantitative manner the different physicochemical properties of the amino acid side chains. In this particular study, hydrophobicity at position 19 was determined to be the dominant property controlling aggregation, while size, charge, and aromaticity had little impact.

Alzheimer\'s disease (AD) and type 2 diabetes mellitus (T2DM) have a common pathology. Both diseases are characterized by local deposition of amyloid proteins in the brain or islet organ, but their phenotypes and clinical manifestation vary widely. Although the sources of islet amyloid polypeptide (IAPP) and amyloid beta (Aβ) are independent, their fibrillar sequences are highly homologous. The prevalence of AD in T2DM populations is considerably higher than that in the normal population, but a mechanistic linkage remains elusive. Therefore, the present study aimed to explore the effects of Aβ42 deposition in the brain on the persistently expression of human IAPP (hIAPP). Additionally, cognitive ability, synaptic plasticity, the state of neural stem cells and mitochondrial function were evaluated at 2 or 6 months after stereotaxically injected the oligomer Aβ1-42 into the dentate gyrus of hIAPP (-/+) mice or the wild-type littermates. We found that Aβ42 and amylin were co-located in hippocampus and Aβ42 levels increased when Aβ1-42 was injected in hIAPP transgenic mice compared with that of the wild-type littermates. Furthermore, at 6 months after Aβ1-42 injection in hIAPP (-/+) mice, it exhibits exacerbated AD-related pathologies including Aβ42 deposition, cognitive impairment, synapse reduction, neural stem cells exhaustion and mitochondrial dysfunction. Our present study suggested that hIAPP directly implicated the Aβ42 production and deposition as an important linkage between T2DM and AD.

Epidemiological studies have linked higher levels of thyroid hormones (THs) to increased risk of Alzheimer\'s disease (AD), whereas in advanced AD, THs have been unchanged or even decreased. In early AD dementia, little is known whether THs are related to AD neuropathology or brain morphology.
This was a cross-sectional study of 36 euthyroid AD patients and 34 healthy controls recruited at a single memory clinic. Levels of THs were measured in serum and cerebrospinal fluid (CSF). In addition, we determined AD biomarkers (amyloid-β1-42, total tau and phosphorylated tau) in CSF and hippocampal and amygdalar volumes using magnetic resonance imaging.
Serum free thyroxine (FT4) levels were elevated, whereas serum free triiodothyronine (FT3)/FT4 and total T3 (TT3)/total T4 (TT4) ratios were decreased, in AD patients compared to controls. In addition, serum TT4 was marginally higher in AD (p = 0.05 vs. the controls). Other TH levels in serum as well as CSF concentrations of THs were similar in both groups, and there were no correlations between THs and CSF AD biomarkers. However, serum FT3 correlated positively with left amygdalar volume in AD patients and serum TT3 correlated positively with left and right hippocampal volume in controls.
Thyroid hormones were moderately altered in mild AD dementia with increased serum FT4, and in addition, the reduced T3/T4 ratios may suggest decreased peripheral conversion of T4 to T3. Furthermore, serum T3 levels were related to brain structures involved in AD development.

Emerging evidence indicates that the enhancement of microglial autophagy inhibits the NLRP3 inflammasome mediated neuroinflammation in Alzheimer\'s disease (AD). Meanwhile, low density lipoprotein receptor-related protein 1 (LRP1) highly expressed in microglia is able to negatively regulate neuroinflammation and positively regulate autophagy. In addition, we have previously reported that an active lychee seed fraction enriching polyphenol (LSP) exhibits anti-neuroinflammation in Aβ-induced BV-2 cells. However, its molecular mechanism of action is still unclear. In this study, we aim to investigate whether LSP inhibits the NLRP3 inflammasome mediated neuroinflammation and clarify its molecular mechanism in Aβ-induced BV-2 cells and APP/PS1 mice. The results showed that LSP dose- and time-dependently activated autophagy by increasing the expression of Beclin 1 and LC3II in BV-2 cells, which was regulated by the upregulation of LRP1 and its mediated AMPK signaling pathway. In addition, both the Western blotting and fluorescence microscopic results demonstrated that LSP could significantly suppress the activation of NLRP3 inflammasome by inhibiting the expression of NLRP3, ASC, the cleavage of caspase-1, and the release of IL-1β in Aβ(1-42)-induced BV-2 cells. In addition, the siRNA LRP1 successfully abolished the effect of LSP on the activation of AMPK and its mediated autophagy, as well as the inhibition of NLRP3 inflammasome. Furthermore, LSP rescued PC-12 cells which were induced by the conditioned medium from Aβ(1-42)-treated BV-2 cells. Moreover, LSP improved the cognitive function and inhibited the NLRP3 inflammasome in APP/PS1 mice. Taken together, LSP inhibited the NLRP3 inflammasome-mediated neuroinflammation in the in vitro and in vivo models of AD, which was closely associated with the LRP1/AMPK-mediated autophagy. Thus, the findings from this study further provide evidences for LSP serving as a potential drug for the treatment of AD in the future.

Alzheimer\'s disease (AD) is a dementing, neurodegenerative disorder characterized by increased accumulation of beta-amyloid peptides (Aβ), degeneration of hippocampal neurons and the gradual development of learning and memory deficits. Therapeutically, there are still no ideal medicines available and this represents an urgent need for the development of new strategies to treat AD. Emerging lines of evidence suggest that modulation of the cannabinoid system exhibits neuroprotective effects in various neurological diseases, including AD. However, a consensus is yet to emerge as to the impact of hippocampal cannabinoid receptor 2 (CB2R) in protection of hippocampal neurons against Aβ induced neuronal toxicity. Here, we report that chronic treatment of primary hippocampal neuronal cultures with 100 nM Aβ1-42 oligomers for 7 days results in neurotoxicity, which includes increases in lactate dehydrogenase (LDH) levels, suggesting an Aβ1-42 -induced neuron apoptosis. Further, chronic Aβ1-42 reduces the ratio of phosphorylated Akt (pAkt)/Akt, in turn decreases neuronal Bcl-2/Bax ratio, and leads to an increase of caspase-3, which likely underlines the signal pathway of chronic Aβ1-42-induced neuron apoptosis. Interestingly, pre-treatments of CB2R agonist (JWH133, 10 μM) with Aβ1-42 prevents Aβ1-42-induced the decrease of pAkt/Akt ratio, the decrease of Bcl-2/Bax ratio, and the increase of caspase-3, and protects hippocampal neurons against Aβ1-42-induced apoptosis. All neuroprotective effects of JWH133 are abolished by a selective CB2R antagonist, AM630. Taken together, the activation of hippocampal CB2Rs protects neurons against Aβ1-42 toxicity, and the CB2R-mediated enhancement of the pAkt signaling is likely involved in the protection of hippocampal neurons against Aβ1-42-induced neuronal toxicity.

Intraneuronal accumulation of amyloid-β (Aβ) is an early pathological signum of Alzheimer\'s disease, and compartments of the endolysosomal system have been implicated in both seeding and cell-cell propagation of Aβ aggregation. We have studied how clathrin-independent mechanisms contribute to Aβ endocytosis, exploring pathways that are sensitive to changes in membrane tension and the regulation of Rho GTPases. Using live cell confocal microscopy and flow cytometry, we show the uptake of monomeric Aβ(1-42) into endocytic vesicles and vacuole-like dilations, following relaxation of osmotic pressure-induced cell membrane tension. This indicates Aβ(1-42) uptake via clathrin independent carriers (CLICs), although overexpression of the bar-domain protein GRAF1, a key regulator of CLICs, had no apparent effect. We furthermore report reduced Aβ(1-42) uptake following overexpression of constitutively active forms of the Rho GTPases Cdc42 and RhoA, whereas modulation of Rac1, which is linked to macropinosome formation, had no effect. Our results confirm that uptake of Aβ(1-42) is clathrin- and dynamin-independent and point to the involvement of a new and distinct clathrin-independent endocytic mechanism which is similar to uptake via CLICs or macropinocytosis but that also appear to involve yet uncharacterized molecular players.

Alzheimer\'s disease (AD) is characterized by the amyloid-beta peptide (Aβ) misfolding to form aberrant amyloid aggregates in the brain. Although recent evidence implicates that amyloid deposition in vivo is highly related to biomembranes, how the characteristic lipid components of neuronal membranes mediate this process remains to be fully elucidated. Herein, we established vesicle models to mimic exosomes and investigated their influence on the kinetics of Aβ(1-42) amyloidosis. By using ternary vesicles composed of three brain lipids monosialoganglioside GM1, cholesterol and sphingomyelin, we found that GM1 could regulate peptide fibrillation by facilitating the conformational transition of Aβ(1-42), and further quantitatively analyzed the influence of GM1-containing vesicles on the kinetics of Aβ(1-42) fibrillation. In addition, GM1-containing vesicles induced the formation of Aβ(1-42) fibrils at low concentrations, and these fibrils were toxic to PC12 cells. By analyzing the role of GM1 in this ternary mixture of membranes at the molecular level, we confirmed that GM1 clusters are presented as attachment sites for peptides, thus promoting the fibrillation of Aβ(1-42).

Progressive memory loss is one of the most common characteristics of Alzheimer\'s disease (AD), which has been shown to be caused by several factors including accumulation of amyloid β peptide (Aβ) plaques and neurofibrillary tangles. Synaptic plasticity and associative plasticity, the cellular basis of memory, are impaired in AD. Recent studies suggest a functional relevance of microRNAs (miRNAs) in regulating plasticity changes in AD, as their differential expressions were reported in many AD brain regions. However, the specific role of these miRNAs in AD has not been elucidated. We have reported earlier that late long-term potentiation (late LTP) and its associative mechanisms such as synaptic tagging and capture (STC) were impaired in Aβ (1-42)-induced AD condition. This study demonstrates that expression of miR-134-5p, a brain-specific miRNA is upregulated in Aβ (1-42)-treated AD hippocampus. Interestingly, the loss of function of miR-134-5p restored late LTP and STC in AD. In AD brains, inhibition of miR-134-5p elevated the expression of plasticity-related proteins (PRPs), cAMP-response-element binding protein (CREB-1) and brain-derived neurotrophic factor (BDNF), which are otherwise downregulated in AD condition. The results provide the first evidence that the miR-134-mediated post-transcriptional regulation of CREB-1 and BDNF is an important molecular mechanism underlying the plasticity deficit in AD; thus demonstrating the critical role of miR-134-5p as a potential therapeutic target for restoring plasticity in AD condition.