Excess Aβ Research Articles

Artemisiae Iwayomogii Herba mitigates excessive neuroinflammation and Aβ accumulation by regulating the pro-inflammatory response and autophagy-lysosomal pathway in microglia in 5xFAD mouse model of Alzheimer's disease.

Alzheimer's disease (AD) presents a growing societal challenge, driven by an aging population. It is characterized by neurodegeneration linked to β-amyloid (Aβ) and tau protein aggregation. Reactive glial cell-mediated neuroinflammation exacerbates disease progression by facilitating the accumulation of Aβ and impairing its clearance, thus highlighting potential therapeutic targets. Aerial parts of Artemisia iwayomogi (AIH), a kind of mugwort, has been consumed as a medicinal herb in East Asia for relieving inflammation-related diseases. Previously, AIH was found to exert potent inhibitory effects on neuroinflammation. This study aimed to examine whether AIH mitigates AD pathogenesis by regulating neuroinflammation and reducing Aβ deposition. AIH treatment to primary mixed glial cultures attenuated the pro-inflammatory responses evoked by Aβ stimulation. When treated to 5 × familial AD (5xFAD) mice, AIH improved learning and cognitive ability and reduced Aβ burden in the brain. AIH suppressed glial overactivation, as well as inhibited the expressions of pro-inflammatory mediators in the brain. Moreover, AIH regulated AKT signaling and elevated the expression of autophagy-lysosomal mediators in vitro. It was confirmed that lysosome-associated membrane protein 1 (LAMP1) was increased in the Aβ-associated microglia in the mouse hippocampus. Finally, it was observed that tau phosphorylation was alleviated, and synaptic protein expression was increased in AIH-treated 5xFAD mice. Overall, this study demonstrated that AIH ameliorated excessive neuroinflammation and Aβ accumulation by regulating microglial activation and autophagy-lysosomal pathway, thereby suggesting AIH as a promising therapeutic candidate for AD treatment.

The dopaminergic system and Alzheimer's disease.

Alzheimer's disease is a common neurodegenerative disorder in older adults. Despite its prevalence, its pathogenesis remains unclear. In addition to the most widely accepted causes, which include excessive amyloid-beta aggregation, tau hyperphosphorylation, and deficiency of the neurotransmitter acetylcholine, numerous studies have shown that the dopaminergic system is also closely associated with the occurrence and development of this condition. Dopamine is a crucial catecholaminergic neurotransmitter in the human body. Dopamine-associated treatments, such as drugs that target dopamine receptor D and dopamine analogs, can improve cognitive function and alleviate psychiatric symptoms as well as ameliorate other clinical manifestations. However, therapeutics targeting the dopaminergic system are associated with various adverse reactions, such as addiction and exacerbation of cognitive impairment. This review summarizes the role of the dopaminergic system in the pathology of Alzheimer's disease, focusing on currently available dopamine-based therapies for this disorder and the common side effects associated with dopamine-related drugs. The aim of this review is to provide insights into the potential connections between the dopaminergic system and Alzheimer's disease, thus helping to clarify the mechanisms underlying the condition and exploring more effective therapeutic options.

Therapeutic effects of a novel synthetic α-secretase.

Excessive accumulation of amyloid-β (Aβ) has been associated with the pathogenesis of Alzheimer's disease (AD). Clinical studies have further proven that elimination of Aβ can be a viable therapeutic option. In the current study, we conceptualized a fusion membrane protein, referred to as synthetic α-secretase (SAS), that can cleave amyloid precursor protein (APP) and Aβ specifically at the α-site. In mammalian cells, SAS indeed cleaved APP and Aβ at the α-site. Overexpression of SAS in the hippocampus was achieved by direct injection of recombinant adeno-associated virus serotype 9 (AAV9) that expresses SAS (AAV9-SAS) into the bilateral ventricles of mouse brains. SAS enhanced the non-amyloidogenic processing of APP, thus reducing the levels of soluble Aβ and plaques in the 5xFAD mice. In addition, SAS significantly attenuated the cognitive deficits in 5xFAD mice, as demonstrated by novel object recognition and Morris water maze tests. Unlike other Aβ-cleaving proteases, SAS has highly strict substrate specificity. We propose that SAS can be an efficient modality to eliminate excessive Aβ from diseased brains.

Role and application of CRISPR-Cas9 in the management of Alzheimer's disease.

Alzheimer's disease (AD) is a serious health issue that has a significant social and economic impact worldwide. One of the key aetiological signs of the disease is a gradual reduction in cognitive function and irreversible neuronal death. According to a 2019 global report, more than 5.8 million people in the United States (USA) alone have received an AD diagnosis, with 45% of those people falling into the 75-84 years age range. According to the predictions, there will be 15 million affected people in the USA by 2050 due to the disease's steadily rising patient population. Cognitive function and memory formation steadily decline as a result of an irreversible neuron loss in AD, a chronic neurodegenerative illness. Amyloid-beta and phosphorylated Tau are produced and accumulate in large amounts, and glial cells are overactive. Additionally, weakened neurotrophin signalling and decreased synapse function are crucial aspects of AD. Memory loss, apathy, depression, and irritability are among the primary symptoms. The aetiology, pathophysiology, and causes of both cognitive decline and synaptic dysfunction are poorly understood despite extensive investigation. CRISPR/Cas9 is a promising gene-editing technique since it can fix certain gene sequences and has a lot of potential for treating AD and other human disorders. Regardless of hereditary considerations, an altered Aβ metabolism is frequently seen in familial and sporadic AD. Therefore, since mutations in the PSEN-1, PSEN-2 and APP genes are a contributing factor to familial AD, CRISPR/Cas9 technology could address excessive Aβ production or mutations in these genes. Overall, the potential of CRISPR-Cas9 technology outweighs it as currently the greatest gene-editing tool available for researching neurodegenerative diseases like AD.

Abstract WP291: Cerebral Amyloid Angiopathy Induces Liver Inflammation in Aged Mice

Introduction: Cerebral amyloid angiopathy (CAA) is a chronic age-related neurodegenerative disease, identified by the presence of amyloid-beta (Aβ) deposition within the vasculature of the brain, leading to stroke and progressive cognitive decline. The liver is a key peripheral organ involved in the clearance of excess Aβ in the circulation. However, the role of the brain-liver axis in CAA is unknown. Here, we investigate inflammatory changes in the liver in a murine model of CAA. Methods: Aged (>23 months) male and female Tg-SwDI (CAA) mice harboring Swedish, Dutch, and Iowa mutations of the human amyloid precursor protein were used as a mouse model of CAA along with age-matched wild-type (WT) controls (n=3-7/grp). Hepatic inflammation was analyzed with histological and immunofluorescence imaging. Single cells from liver tissue were isolated and analyzed using flow cytometry. Total RNA was isolated to examine gene expression in the liver using real-time quantitative PCR. Results: Our data showed that CAA increases infiltration of immune cells proximal to liver sinusoids across both sexes compared to WT mice. We found increased macrophages (i.e., F4/80 + cells) in the liver of CAA mice compared to WT controls. Flow cytometry on the liver revealed that female CAA mice had a significant increase in dendritic cells (i.e., CD80 + CD45 + CD11c + cells, *** P <0.001) compared to WT females. Further, we found that Oatp2 , a membrane transporter which mediates hepatocytic uptake of toxic molecules (e.g., Aβ), is associated with sex-specific CAA pathophysiology in the liver. Conclusions: In this study, we found that sex differences may exist in CAA-induced liver inflammation. Further investigations are needed to study how vascular amyloidosis shapes the immune responses and peripheral Aβ clearance in the context of aging and CAA.

Intestinal changes in permeability, tight junction and mucin synthesis in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid‑β (Aβ) in the brain. The gut/brain axis may serve a role in AD pathogenesis. The present study investigated deposition of Aβ in the intestinal epithelium and its potential effects on intestinal barrier function in a transgenic mouse model of AD. To investigate alterations in the structure and functionality of the intestinal mucosal barrier in AD model mice, hematoxylin and eosin staining for Paneth cell count, Alcian blue‑periodic acid Schiff staining for goblet cells, immunohistochemistry and immunofluorescence for mucin (MUC)2 and wheat germ agglutin expression, transmission electron microscopy for mucosal ultrastructure, FITC‑labeled dextran assay for intestinal permeability, quantitative PCR for goblet cell precursor expression and western blot analysis for tight junction proteins, MUC2 and inflammatory cytokine detection were performed. The results showed that AD model mice exhibited excessive Aβ deposition in the intestinal epithelium, which was accompanied by increased intestinal permeability, inflammatory changes and decreased expression of tight junction proteins. These alterations in the intestinal barrier led to an increased proliferation of goblet and Paneth cells and increased mucus synthesis. Dysfunction of gut barrier occurs in AD and may contribute to its etiology. Future therapeutic strategies to reverse AD pathology may involve early manipulation of gut physiology and its microbiota.

Neurodevelopmental disorders and microcephaly: how apoptosis, the cell cycle, tau and amyloid-β precursor protein APPly.

Recent studies promote new interest in the intersectionality between autism spectrum disorder (ASD) and Alzheimer's Disease. We have reported high levels of Amyloid-β Precursor Protein (APP) and secreted APP-alpha (sAPP) and low levels of amyloid-beta (Aβ) peptides 1-40 and 1-42 (Aβ40, Aβ42) in plasma and brain tissue from children with ASD. A higher incidence of microcephaly (head circumference less than the 3rd percentile) associates with ASD compared to head size in individuals with typical development. The role of Aβ peptides as contributors to acquired microcephaly in ASD is proposed. Aβ may lead to microcephaly via disruption of neurogenesis, elongation of the G1/S cell cycle, and arrested cell cycle promoting apoptosis. As the APP gene exists on Chromosome 21, excess Aβ peptides occur in Trisomy 21-T21 (Down's Syndrome). Microcephaly and some forms of ASD associate with T21, and therefore potential mechanisms underlying these associations will be examined in this review. Aβ peptides' role in other neurodevelopmental disorders that feature ASD and acquired microcephaly are reviewed, including dup 15q11.2-q13, Angelman and Rett syndrome.

Yuanzhi powder facilitated Aβ clearance in APP/PS1 mice: Target to the drainage of glymphatic system and meningeal lymphatic vessels

Ethnopharmacological relevanceYuanzhi Powder (YZP) is a classical Chinese medicine prescription, which is suitable for the treatment of dementia by “dispelling phlegm and opening orifice”. The therapeutic efficacy of YZP on Alzheimer's disease (AD) has been previously reported in our work. However, it remains unclear whether the neuroprotective effect of YZP is linked to β-amyloid(Aβ) clearance through cerebral lymphatic drainage. Aim of the studyThe aim was to determine the protective efficacy of YZP against AD and investigate the potential mechanism for eliminating excessive Aβ deposition. Materials and methodsAPP/PS1 mice were divided into four groups of 8 mice each: APP/PS1 group, DONE group, L-YZP group, and H-YZP group. Additionally, 8 wild-type littermates were assigned to the control group (WT group). After 8 weeks of consecutive intragastric administration, behavioral tests, including the open field test, novel object recognition test and Morris Water Maze test, were employed to assess the cognitive abilities of all groups of mice. Nissl staining, immunohistochemistry, and western blotting were utilized to evaluate clearance of excessive Aβ deposition and pathological changes. Furthermore, immunofluorescence was applied to visualize the drainage of the cerebral lymphatic system after fluorescent tracer injection in the cisterna magna. ResultsThe administration of YZP significantly attenuated cognitive deficits, cleared excessive Aβ deposition, and improved pathological damage in APP/PS1 mice. Furthermore, YZP effectively enhanced glymphatic system drainage by restoring AQP4 polarization and inhibiting reactive astrogliosis. Additionally, YZP facilitated the drainage of meningeal lymphatic vessels (MLVs) by augmenting their diameter and coverage. Lastly, YZP promoted the elimination of Aβ from the brain to deep cervical lymph nodes. ConclusionsThe administration of YZP may ameliorate the cognitive deficits and pathological damage in APP/PS1 mice by effectively clearing excessive Aβ deposition. The underlying mechanisms potentially involve Aβ clearance through the cerebral lymphatic system, which includes the glymphatic system and MLVs.

ROS-responsive nanomodulators downregulate IFITM3 expression and eliminate ROS for Alzheimer’s disease combination treatment

Neuronal damage caused by β-amyloid (Aβ) aggregates and excess reactive oxygen species (ROS) is a crucial pathogenic event in Alzheimer's disease (AD). However, current Aβ-targeting RNA interference (RNAi) treatments have shown limited therapeutic efficacy due to ineffective intracerebral siRNA delivery and overlooked crosstalk between excess ROS and Aβ aggregates in the brain. Herein, a ROS-responsive nanomodulator (NM/CM) was developed for the combinational treatment of RNAi and ROS elimination for AD. NM/CM was coated with 4T1 cell membranes, which endowed NM/CM with the capability to cross blood–brain barrier (BBB). After being internalized by neural cells, NM/CM releases curcumin (Cur) and siIFITM3 spontaneously into the cytoplasm. The released Cur can eliminate ROS, protecting neurons from oxidative damage and reducing the production of Aβ induced by ROS-related neuroinflammation. The released siIFITM3 can downregulate the expression of interferon-induced transmembrane protein 3 (IFITM3), thereby reducing the abnormal Aβ production mediated by IFITM3. As a result, NM/CM remarkably alleviated ROS- and Aβ aggregate-induced neurotoxicity in vitro, showing significant neuroprotective effects. This work demonstrates the potential of NM/CM in the development of novel and effective AD combination therapies.

Structural and metabolic brain correlates of excess Aβ accumulation at the earliest AD continuum

AbstractBackgroundThe discrepancy between the expected and actual level of cerebral amyloid (Aβ) deposition for any given level of soluble Alzheimer’s disease (AD) core biomarkers, has been proposed as a proxy measure of factors promoting fibrillar Aβ accumulation in the brain. However, the impact of these factors on brain structure and function in cognitively unimpaired (CU) individuals has not been reported. Here, we assessed the impact on brain structure and metabolism of the excess cortical Aβ deposition for a given level of CSF pTau/Aβ42 ratio, a marker of pathophysiological progression along the Alzheimer’s continuum. Furthermore, we analyzed whether this association is modulated by the APOE‐ε4 risk allele.MethodWe included 243 CU participants from the ALFA study (mean age=61.68 years) who underwent a lumbar puncture, magnetic resonance imaging (MRI), 18F‐Fluorodeoxyglucose (FDG) and 18F‐Flutemetamol positron emission tomography (PET) scans. CSF Aβ42 and pTau181 were measured with the Elecsys® immunoassay (Roche Diagnostics International Ltd). The centiloid pipeline was applied to Aβ PET and a general linear model (GLM) was implemented to regress out the effects of CSF pTau/Aβ42 ratio from centiloid values. These residualized centiloids (resCent) were used in subsequent GLMs to predict whole‐brain gray matter volume (GMv) as well as metabolism. Statistical significance threshold was set to p<0.005, with a cluster extent correction of 100 voxels.ResultNegative associations between resCent and GMv were observed in the dorsolateral prefrontal cortex (Fig. 1a), while for FDG, positive associations were found in the inferior frontal and superior temporal gyrus, as well as the anterior cingulate and inferior temporal cortices (Fig. 1b). The associations for GMv were further modulated by the APOE‐ε4 risk allele in a dose‐dependent manner, indicating a lower GMv in ε4‐carriers, in the inferior and middle frontal gyrus, subgenual cingulate cortex and the insula (Fig. 2).ConclusionOur results suggest that, factors associated with excessive Aβ deposition are associated with structural and metabolic brain alterations already in the earliest stages of preclinical Alzheimer’s continuum. The associations for GMv were modulated by APOE‐ε4 indicating a higher structural vulnerability to these factors for carriers of the risk allele all along the preclinical stages of AD.

Effects and mechanism of Aβ1−42 on EV-A71 replication

Backgroundβ-Amyloid (Aβ) protein is a pivotal pathogenetic factor in Alzheimer’s disease (AD). However, increasing evidence suggests that the brain has to continuously produce excessive Aβ to efficaciously prevent pathogenic micro-organism infections, which induces and accelerates the disease process of AD. Meanwhile, Aβ exhibits activity against herpes simplex virus type 1 (HSV-1) and influenza A virus (IAV) replication, but not against other neurotropic viruses. Enterovirus A71 (EV-A71) is the most important neurotropic enterovirus in the post-polio era. Given the limitation of existing research on the relationship between Aβ and other virus infections, this study aimed to investigate the potent activity of Aβ on EV-A71 infection and extended the potential function of Aβ in other unenveloped viruses may be linked to Alzheimer's disease or infectious neurological diseases.MethodsAβ peptides 1–42 are a major pathological factor of senile plaques in Alzheimer’s disease (AD). Thus, we utilized Aβ1–42 as a test subject to perform our study. The production of monomer Aβ1–42 and their high-molecular oligomer accumulations in neural cells were detected by immunofluorescence assay, ELISA, or Western blot assay. The inhibitory activity of Aβ1–42 peptides against EV-A71 in vitro was detected by Western blot analysis or qRT-PCR. The mechanism of Aβ1–42 against EV-A71 replication was analyzed by time-of-addition assay, attachment inhibition assay, pre-attachment inhibition analysis, viral-penetration inhibition assay, TEM analysis of virus agglutination, and pull-down assay.ResultsWe found that EV-A71 infection induced Aβ production and accumulation in SH-SY5Y cells. We also revealed for the first time that Aβ1–42 efficiently inhibited the RNA level of EV-A71 VP1, and the protein levels of VP1, VP2, and nonstructural protein 3AB in SH-SY5Y, Vero, and human rhabdomyosarcoma (RD) cells. Mechanistically, we demonstrated that Aβ1–42 primarily targeted the early stage of EV-A71 entry to inhibit virus replication by binding virus capsid protein VP1 or scavenger receptor class B member 2. Moreover, Aβ1–42 formed non-enveloped EV-A71 particle aggregates within a certain period and bound to the capsid protein VP1, which partially caused Aβ1–42 to prevent viruses from infecting cells.ConclusionsOur findings unveiled that Aβ1–42 effectively inhibited nonenveloped EV-A71 by targeting the early phase of an EV-A71 life cycle, thereby extending the potential function of Aβ in other non-envelope viruses linked to infectious neurological diseases.

The Amyloid Cascade Hypothesis 2.0: On the Possibility of Once-in-a-Lifetime-Only Treatment for Prevention of Alzheimer's Disease and for Its Potential Cure at Symptomatic Stages.

We posit that Alzheimer’s disease (AD) is driven by amyloid-β (Aβ) generated in the amyloid-β protein precursor (AβPP) independent pathway activated by AβPP-derived Aβ accumulated intraneuronally in a life-long process. This interpretation constitutes the Amyloid Cascade Hypothesis 2.0 (ACH2.0). It defines a tandem intraneuronal-Aβ (iAβ)-anchored cascade occurrence: intraneuronally-accumulated, AβPP-derived iAβ triggers relatively benign cascade that activates the AβPP-independent iAβ-generating pathway, which, in turn, initiates the second, devastating cascade that includes tau pathology and leads to neuronal loss. The entire output of the AβPP-independent iAβ-generating pathway is retained intraneuronally and perpetuates the pathway’s operation. This process constitutes a self-propagating, autonomous engine that drives AD and ultimately kills its host cells. Once activated, the AD Engine is self-reliant and independent from Aβ production in the AβPP proteolytic pathway; operation of the former renders the latter irrelevant to the progression of AD by relegating its iAβ contribution to insignificant, and brands its manipulation for therapeutic purposes, such as BACE (beta-site AβPP-cleaving enzyme) inhibition, as futile. In the proposed AD paradigm, the only valid direct therapeutic strategy is targeting the engine’s components, and the most effective feasible approach appears to be the activation of BACE1 and/or of its homolog BACE2, with the aim of exploiting their Aβ-cleaving activities. Such treatment would collapse the iAβ population and ‘reset’ its levels below those required for the operation of the AD Engine. Any sufficiently selective iAβ-depleting treatment would be equally effective. Remarkably, this approach opens the possibility of a short-duration, once-in-a-lifetime-only or very infrequent, preventive or curative therapy for AD; this therapy would be also effective for prevention and treatment of the ‘common’ pervasive aging-associated cognitive decline. The ACH2.0 clarifies all ACH-unresolved inconsistencies, explains the widespread ‘resilience to AD’ phenomenon, predicts occurrences of a category of AD-afflicted individuals without excessive Aβ plaque load and of a novel type of familial insusceptibility to AD; it also predicts the lifespan-dependent inevitability of AD in humans if untreated preventively. The article details strategy and methodology to generate an adequate AD model and validate the hypothesis; the proposed AD model may also serve as a research and drug development platform.

A New Hypothesis for Alzheimer's Disease: The Lipid Invasion Model.

This paper proposes a new hypothesis for Alzheimer’s disease (AD)—the lipid invasion model. It argues that AD results from external influx of free fatty acids (FFAs) and lipid-rich lipoproteins into the brain, following disruption of the blood-brain barrier (BBB). The lipid invasion model explains how the influx of albumin-bound FFAs via a disrupted BBB induces bioenergetic changes and oxidative stress, stimulates microglia-driven neuroinflammation, and causes anterograde amnesia. It also explains how the influx of external lipoproteins, which are much larger and more lipid-rich, especially more cholesterol-rich, than those normally present in the brain, causes endosomal-lysosomal abnormalities and overproduction of the peptide amyloid-β (Aβ). This leads to the formation of amyloid plaques and neurofibrillary tangles, the most well-known hallmarks of AD. The lipid invasion model argues that a key role of the BBB is protecting the brain from external lipid access. It shows how the BBB can be damaged by excess Aβ, as well as by most other known risk factors for AD, including aging, apolipoprotein E4 (APOE4), and lifestyle factors such as hypertension, smoking, obesity, diabetes, chronic sleep deprivation, stress, and head injury. The lipid invasion model gives a new rationale for what we already know about AD, explaining its many associated risk factors and neuropathologies, including some that are less well-accounted for in other explanations of AD. It offers new insights and suggests new ways to prevent, detect, and treat this destructive disease and potentially other neurodegenerative diseases.

The relationship between amyloid-beta and brain capillary endothelial cells in Alzheimer's disease.

Neurovascular dysfunction, as an integral part of Alzheimer’s disease, may have an important influence on the onset and progression of chronic neurodegenerative processes. The blood-brain barrier (BBB) pathway is one of the main pathways that mediates the clearance of amyloid-beta (Aβ) in the brain parenchyma. A large number of studies have shown that receptors and ATP-binding cassette transporters expressed on endothelial cells play an important role in Aβ transport across the BBB, but the specific mechanism is not clear. In this review, we summarize the possible mechanisms of Aβ production and clearance, and in particular the relationship between Aβ and brain capillary endothelial cells. Aβ is produced by abnormal cleavage of the amyloid precursor protein via amyloidogenic processing under pathological conditions. Dysregulation of Aβ clearance is considered to be the main reason for the massive accumulation of Aβ in the brain parenchyma. Several pathways mediating Aβ clearance from the brain into the periphery have been identified, including the BBB pathway, the blood-cerebrospinal fluid barrier and arachnoid granule pathway, and the lymphoid-related pathway. Brain capillary endothelial cells are the key components of Aβ clearance mediated by BBB. Receptors (such as LRP1, RAGE, and FcRn) and ATP-binding cassette transporters (such as P-gp, ABCA1, and ABCC1) expressed on endothelial cells play a critical role in Aβ transcytosis across the BBB. The toxic effects of Aβ can induce dysregulation of receptor and transporter expression on endothelial cells. Excessive Aβ exerts potent detrimental cerebrovascular effects by promoting oxidative stress, inducing chronic inflammation, and impairing endothelial structure and functions. All of these are main causes for the reduction in Aβ clearance across the BBB and the accumulation of Aβ in the brain parenchyma. Therefore, studies on the interactions between Aβ and brain capillary endothelial cells, including their receptors and transporters, studies on inhibition of the toxic effects of Aβ on endothelial cells, and studies on promoting the ability of endothelial cells to mediate Aβ clearance may provide new therapeutic strategies for Aβ clearance in Alzheimer’s disease.

Amyloid beta’s antimicrobial properties protect elderly mice from succumbing to infection with the neurotropic parasite Toxoplasma gondii

Data suggest that amyloid beta (Aβ) is a major initiator of Alzheimer's disease (AD) and a highly conserved anti-microbial peptide. Although Aβ accumulation is thought to be detrimental to the brain as a trigger of pathology, like neuroinflammation, efforts to cure AD by clearing Aβ have failed in part because the reactivation of latent disease. Thus, more work is needed to understand how Aβ may be necessary to the brain, where the actions of the adaptive immune system are more restricted compared to other organs in the body. Using the intracellular T.gondii, we are exploring how infection impacts Aβ levels in the brain, how Aβ may combat the parasite, and whether Aβ's importance may change as organisms age.To address whether Aβ is an effective antimicrobial peptide in response to T.gondii infection, in vitro experiments were performed to determine if and how Aβ may protect against infection. Further, in vivo infection studies were performed to assess whether the presence of excess Aβ is helpful during infection with respect to age.We found that exposure to Aβ is effective at protecting cells from invasion by the parasite and those parasites replicate more slowly within cells once they do invade. In vivo, mice with excess Aβ have a lower parasite burden in the brain, indicating that Aβ may either help protect the brain from colonization by an invading pathogen or can help clear the brain of pathogens that have breached the blood-brain barrier. Further, we have found that these protective effects are only beneficial to elderly mice as aged (18mo+) mice with excess Aβ are able to survive T.gondii infection, while their WT littermates are not.These data support the idea that the Aβ could be beneficial as we age. Current work is focused on whether Aβ is toxic to T.gondii or if, as seen in viruses, Aβ traps the pathogen, making it more vulnerable to clearance by the immune system. Future work will include examining how Aβ impacts the functions of the immune system and how pathogens like T.gondii may have evolved ways to subvert the antimicrobial actions of Aβ.

The Function and Expression of ATP-Binding Cassette Transporters Proteins in the Alzheimer's Disease.

Despite many years of research, radical treatment of Alzheimer's disease (AD) has still not been found. Amyloid-β (Aβ) peptide is known to play an important role in the pathogenesis of this disease. AD is characterized by three main changes occurring in the central nervous system: (1) Aβ plaque accumulation that prevents synaptic communication, (2) the accumulation of hyperphosphorylated tau proteins that inhibit the transport of molecules inside neurons, and (3) neuronal cell loss of the limbic system. Mechanisms leading to Aβ accumulation in AD are excessive Aβ production as a result of mutations in amyloid precursor protein or genes, and impairment of clearance of Aβ due to changes in Aβ aggregation properties and/or Aβ removal processes. Human ATP-binding cassette (ABC) transporters are expressed in astrocyte, microglia, neuron, brain capillary endothelial cell, choroid plexus, choroid plexus epithelial cell, and ventricular ependymal cell. ABC transporters have essential detoxification and neuroprotective roles in the brain. The expression and functional changes in ABC transporters contribute to the accumulation of Aβ peptide. In conclusion, the review was aimed to summarize and highlight accumulated evidence in the literature focusing on the changing functions of human ABC transporter members, in AD pathogenesis and progression.

New Evidence for P-gp-Mediated Export of Amyloid-β PEPTIDES in Molecular, Blood-Brain Barrier and Neuronal Models.

Defective clearance mechanisms lead to the accumulation of amyloid-beta (Aβ) peptides in the Alzheimer’s brain. Though predominantly generated in neurons, little is known about how these hydrophobic, aggregation-prone, and tightly membrane-associated peptides exit into the extracellular space where they deposit and propagate neurotoxicity. The ability for P-glycoprotein (P-gp), an ATP-binding cassette (ABC) transporter, to export Aβ across the blood-brain barrier (BBB) has previously been reported. However, controversies surrounding the P-gp–Aβ interaction persist. Here, molecular data affirm that both Aβ40 and Aβ42 peptide isoforms directly interact with and are substrates of P-gp. This was reinforced ex vivo by the inhibition of Aβ42 transport in brain capillaries from P-gp-knockout mice. Moreover, we explored whether P-gp could exert the same role in neurons. Comparison between non-neuronal CHO-APP and human neuroblastoma SK-N-SH cells revealed that P-gp is expressed and active in both cell types. Inhibiting P-gp activity using verapamil and nicardipine impaired Aβ40 and Aβ42 secretion from both cell types, as determined by ELISA. Collectively, these findings implicate P-gp in Aβ export from neurons, as well as across the BBB endothelium, and suggest that restoring or enhancing P-gp function could be a viable therapeutic approach for removing excess Aβ out of the brain in Alzheimer’s disease.

Quinovic Acid Impedes Cholesterol Dyshomeostasis, Oxidative Stress, and Neurodegeneration in an Amyloid-β-Induced Mouse Model.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder typified by several neuropathological features including amyloid-beta (Aβ) plaque and neurofibrillary tangles (NFTs). Cholesterol retention and oxidative stress (OS) are the major contributors of elevated β- and γ-secretase activities, leading to excessive Aβ deposition, signifying the importance of altered cholesterol homeostasis and OS in the progression of Aβ-mediated neurodegeneration and cognitive deficit. However, the effect of Aβ on cholesterol metabolism is lesser-known. In this study, we evaluated the effect of quinovic acid (QA; 50 mg/kg body weight, i.p.) against the intracerebroventricular (i.c.v.) injection of Aβ (1-42)-induced cholesterol dyshomeostasis, oxidative stress, and neurodegeneration in the cortex and hippocampal brain regions of wild-type male C57BL/6J mice. Our results indicated that Aβ (1-42)-treated mice have increased Aβ oligomer formation along with increased β-secretase expression. The enhanced amyloidogenic pathway in Aβ (1-42)-treated mice intensified brain cholesterol accumulation due to increased expressions of p53 and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) enzyme. Importantly, we further confirmed the p53-mediated HMGCR axis activation by using pifithrin-α (PFT) in SH-SY5Y cells. Furthermore, the augmented brain cholesterol levels were also associated with increased OS. However, the QA administration to Aβ (1-42)-injected mice significantly ameliorated the Aβ burden, p53 expression, and cholesterol accumulation by deterring the oxidative stress through upregulating the Nrf2/HO-1 pathway. Moreover, the QA downregulated gliosis, neuroinflammatory mediators (p-NF-κB and IL-1β), and the expression of mitochondrial apoptotic markers (Bax, cleaved caspase-3, and cytochrome c). QA treatment also reversed the deregulated synaptic markers (PSD-95 and synaptophysin) and improved spatial learning and memory behaviors in the Aβ-treated mouse brains. These results suggest that Aβ (1-42) induces its acute detrimental effects on cognitive functions probably by increasing brain cholesterol levels through a possible activation of the p53/HMGCR axis. However, QA treatment reduces the cholesterol-induced oxidative stress, neuroinflammation, and neurodegeneration, leading to the restoration of cognitive deficit after Aβ (1-42) i.c.v. injection in mice.

Novel therapeutic strategies for Alzheimer's disease targeting brain cholesterol homeostasis.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. Aβ plaques and tauopathy are two major concerns associated with AD. Moreover, excessive Aβ accumulation can lead to other nonspecific metabolic brain abnormalities. There are various genetic, environmental, and other risk factors associated with AD. Identification of risk factors and its mechanisms by which these factors impart role in AD pathology would be helpful for the prevention of AD progression. Altered cholesterol homeostasis could be considered as a risk factor for AD progression. Brain cholesterol dysmetabolism is recognized as one of the crucial attributes for AD that affect major hallmarks of AD including neurodegeneration. To fill the gap between altered cholesterol levels in the brain and AD, the researchers started focusing on statins as re-purposing drugs for AD treatment. The various other hypothesis has been suggested due to a lack of beneficial results of statins in clinical trials, such as reduced brain cholesterol could underlie poor cognition. Unfortunately, it is still unclear, whether an increase or decrease in brain cholesterol levels responsible for Alzheimer's disease or not. Presently, scientists believed that managing the level of cholesterol in the brain may help as an alternative treatment strategy for AD. In this review, we focused on the therapeutic strategies for AD by targeting brain cholesterol levels.

Immune and Inflammatory Determinants Underlying Alzheimer’s Disease Pathology

This study examines the link between peripheral immune changes in perpetuation of the Alzheimer's disease (AD) neuropathology and cognitive deficits. Our research design using human AD patients and rodent model is supported by past evidence from genomic studies. We observed an active immune response against Aβ as indicated by the increased Aβ specific IgG antibody in the serum of AD and patients with mild cognitive impairments as compared to healthy controls. A similar increase in IgG and decrease in IgM antibody against Aβ was also confirmed in the 5xFAD mouse model of AD. More importantly, we observed a negative correlation between reduced IgM levels and cognitive dysfunction that manifested as impaired memory consolidation. Strong peripheral immune activation was supported by increased activation of microglia in the brain and macrophages in the spleen of AD mice compared to wild type control littermates. Furthermore, inflammatory cytokine IL-21 that is involved in antibody class switching was elevated in the plasma of AD patients and correlated positively with the IgG antibody levels. Concurrently, an increase in IL-21 and IL-17 was observed in spleen cells from AD mice. Further investigation revealed that proportions of T follicular helper (Tfh) cells that secrete IL-21 are increased in the spleen of AD mice. In contrast to Tfh, the frequency of B1 cells that produce IgM antibodies was reduced in AD mice. Altogether, these data indicate that in AD the immune tolerance to Aβ is compromised leading to chronic immune/inflammatory responses against Aβ that are detrimental and cause neuropathology. Graphical Abstract Healthy subjects are tolerant to Aβ and usually react weakly to it resulting the in the production of IgM class of antibodies that are efficient at clearing up self-antigens such as Aβ without causing inflammation. In contrast, Alzheimer's disease patients mount a strong immune response against Aβ probably in an effort to clear up excessive Aβ. There is enhanced production of inflammatory cytokines such as IL-21 as well as an increase in Tfh cells that cause antibody class switching form IgM to IgG. The strong immune response is inefficient at clearing up Aβ and instead exacerbates inflammation that causes AD neuropathology and cognitive dysfunction.