Pathological Changes Of Alzheimer's Disease Research Articles

Analysis of early diagnosis methods for asymmetric dementia in brain MR images based on genetic medical technology.

Alzheimer's disease (AD) is a relatively common senile neurodegenerative disease and the main manifestation of senile dementia. In the pathological changes of AD, the asymmetry of the brain also changes. Therefore, finding an early diagnosis method of AD based on asymmetry is the key to the treatment of Alzheimer's. Magnetic resonance (MR) imaging can quantitatively reflect the structural and functional changes of various tissues in the brain. It has the advantages of non-invasive, high spatial resolution, and non-radiation, and has been widely used in the early diagnosis of AD. In this work, asymmetric images were extracted from multiple brain MR images, and different morphological and texture features were extracted. By establishing a feature selection classification integration model, image features in the image were deeply fused to obtain higher and more stable recognition results than before. By filtering image samples, the corresponding sample feature matrix was obtained. Support vector machine was used for classification, and its classification accuracy had improved significantly compared with that before selection. In the experimental data of normal control group and AD group, the accuracy, sensitivity, and specificity of the feature selection algorithm were 93.34, 90.69, and 95.87%, respectively. In the normal control group and the mild cognitive impairment group, the accuracy, sensitivity, and specificity of the feature selection algorithm in this work were 85.31, 79.68, and 88.54%, respectively. On the whole, the classification accuracy of the feature selection algorithm in this work was much higher than that of other items. In addition, from the classification ability and distribution of asymmetric features, it can be seen that this asymmetric feature had a more significant consistent diagnostic role in clinical practice.

Sensory processing deficits and related cortical pathological changes in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily affecting cognitive functions. However, sensory deficits in AD start to draw attention due to their high prevalence and early onsets which suggest that they could potentially serve as diagnostic biomarkers and even contribute to the disease progression. This literature review examines the sensory deficits and cortical pathological changes observed in visual, auditory, olfactory, and somatosensory systems in AD patients, as well as in various AD animal models. Sensory deficits may emerge at the early stages of AD, or even precede the cognitive decline, which is accompanied by cortical pathological changes including amyloid-beta deposition, tauopathy, gliosis, and alterations in neuronal excitability, synaptic inputs, and functional plasticity. Notably, these changes are more pronounced in sensory association areas and superficial cortical layers, which may explain the relative preservation of basic sensory functions but early display of deficits of higher sensory functions. We propose that sensory impairment and the progression of AD may establish a cyclical relationship that mutually perpetuates each condition. This review highlights the significance of sensory deficits with or without cortical pathological changes in AD and emphasizes the need for further research to develop reliable early detection and intervention through sensory systems.

Skeletal muscle mitochondrial function predicts cognitive impairment and is associated with biomarkers of Alzheimer's disease and neurodegeneration.

Mitochondrial dysfunction is implicated in the pathophysiology of many chronic diseases. Whether it is related to cognitive impairment and pathological markers is unknown. We examined the associations of in vivo skeletal muscle mitochondrial function (post-exercise recovery rate of phosphocreatine [kPCr] via magnetic resonance [MR] spectroscopy with future mild cognitive impairment (MCI) or dementia, and with positron emission tomography (PET) and blood biomarkers of Alzheimer's disease [AD] and neurodegeneration (i.e., Pittsburgh Compound-B [PiB] distribution volume ratio [DVR] for amyloid beta [Aβ], flortaucipir (FTP) standardized uptake value ratio [SUVR] for tau, Aβ42 /40 ratio, phosphorylated tau 181 [p-tau181], neurofilament light chain [NfL], and glial fibrillary acidic protein [GFAP]). After covariate adjustment, each standard deviation (SD) higher kPCr level was associated with 52% lower hazards of developing MCI/dementia, and with 59% lower odds of being PiB positive with specific associations in DVR of frontal, parietal, and temporal regions, and cingulate cortex and pallidum. Higher kPCr level was also associated with lower plasma GFAP. In aging, mitochondrial dysfunction may play a vital role in AD pathological changes and neuroinflammation. Highlights Higher in vivo mitochondrial function is related to lower risk of mild cognitive impairment (MCI)/dementia. Higher in vivo mitochondrial function is related to lower amyloid tracer uptake. Higher in vivo mitochondrial function is related to lower plasma neuroinflammation. Mitochondrial dysfunction may play a key role in Alzheimer's disease (AD) and neurodegeneration.

Soluble TREM2 Concentrations in the Cerebrospinal Fluid Correlate with the Severity of Neurofibrillary Degeneration, Cognitive Impairment, and Inflammasome Activation in Alzheimer's Disease.

Individuals with specific TREM2 gene variants that encode for a Triggering Receptor Expressed on Myeloid cells 2 have a higher prevalence of Alzheimer's disease (AD). By interacting with amyloid and apolipoproteins, the TREM2 receptor regulates the number of myeloid cells, phagocytosis, and the inflammatory response. Higher TREM2 expression has been suggested to protect against AD. However, it is extremely difficult to comprehend TREM2 signaling in the context of AD. Previous results are variable and show distinct effects on diverse pathological changes in AD, differences between soluble and membrane isoform signaling, and inconsistency between animal models and humans. In addition, the relationship between TREM2 and inflammasome activation pathways is not yet entirely understood. This study aimed to determine the relationship between soluble TREM2 (sTREM2) levels in cerebrospinal fluid (CSF) and plasma samples and other indicators of AD pathology. Using the Enzyme-Linked Immunosorbent Assay (ELISA), we analyzed 98 samples of AD plasma, 35 samples of plasma from individuals with mild cognitive impairment (MCI), and 11 samples of plasma from healthy controls (HC), as well as 155 samples of AD CSF, 90 samples of MCI CSF, and 50 samples of HC CSF. CSF sTREM2 levels were significantly correlated with neurofibrillary degeneration, cognitive decline, and inflammasome activity in AD patients. In contrast to plasma sTREM2, CSF sTREM2 levels in the AD group were higher than those in the MCI and HC groups. Moreover, concentrations of sTREM2 in CSF were substantially higher in the MCI group than in the HC group, indicating that CSF sTREM2 levels could be used not only to distinguish between HC and AD patients but also as a biomarker to detect earlier changes in the MCI stage. The results indicate CSF sTREM2 levels reliably predict neurofibrillary degeneration, cognitive decline, and inflammasome activation, and also have a high diagnostic potential for distinguishing diseased from healthy individuals. To add sTREM2 to the list of required AD biomarkers, future studies will need to include a larger number of patients and utilize a standardized methodology.

Intranasally administered extracellular vesicles from human induced pluripotent stem cell-derived neural stem cells quickly incorporate into neurons and microglia in 5xFAD mice.

Extracellular vesicles (EVs) released by human-induced pluripotent stem cell (hiPSC)-derived neural stem cells (NSCs) have robust antiinflammatory and neurogenic properties due to therapeutic miRNAs and proteins in their cargo. Hence, hiPSC-NSC-EVs are potentially an excellent biologic for treating neurodegenerative disorders, including Alzheimer's disease (AD). This study investigated whether intranasally (IN) administered hiPSC-NSC-EVs would quickly target various neural cell types in the forebrain, midbrain, and hindbrain regions of 3-month-old 5xFAD mice, a model of β-amyloidosis and familial AD. We administered a single dose of 25 × 109 hiPSC-NSC-EVs labeled with PKH26, and different cohorts of naïve and 5xFAD mice receiving EVs were euthanized at 45 min or 6 h post-administration. At 45 min post-administration, EVs were found in virtually all subregions of the forebrain, midbrain, and hindbrain of naïve and 5xFAD mice, with predominant targeting and internalization into neurons, interneurons, and microglia, including plaque-associated microglia in 5xFAD mice. EVs also came in contact with the plasma membranes of astrocytic processes and the soma of oligodendrocytes in white matter regions. Evaluation of CD63/CD81 expression with the neuronal marker confirmed that PKH26 + particles found within neurons were IN administered hiPSC-NSC-EVs. At 6 h post-administration, EVs persisted in all cell types in both groups, with the distribution mostly matching what was observed at 45 min post-administration. Area fraction (AF) analysis revealed that, in both naïve and 5xFAD mice, higher fractions of EVs incorporate into forebrain regions at both time points. However, at 45 min post-IN administration, AFs of EVs within cell layers in forebrain regions and within microglia in midbrain and hindbrain regions were lower in 5xFAD mice than naïve mice, implying that amyloidosis reduces EV penetrance. Collectively, the results provide novel evidence that IN administration of therapeutic hiPSC-NSC-EVs is an efficient avenue for directing such EVs into neurons and glia in all brain regions in the early stage of amyloidosis. As pathological changes in AD are observed in multiple brain areas, the ability to deliver therapeutic EVs into various neural cells in virtually every brain region in the early stage of amyloidosis is attractive for promoting neuroprotective and antiinflammatory effects.

Various Energetic Metabolism of Microglia in Response to Different Stimulations.

The activation of the microglia plays an important role in the neuroinflammation induced by different stimulations associated with Alzheimer's disease (AD). Different stimulations, such as pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) and cytokines, trigger a consequence of activation in the microglia with diverse changes of the microglial cell type response in AD. The activation of the microglia is often accompanied by metabolic changes in response to PAMPs, DAMPs and cytokines in AD. Actually, we do not know the distinct differences on the energetic metabolism of microglia when subject to these stimuli. This research assessed the changes of the cell type response and energetic metabolism in mouse-derived immortalized cells (BV-2 cells) induced by a PAMP (LPS), DAMPs (Aβ and ATP) and a cytokine (IL-4) in mouse-derived immortalized cells (BV-2 cells) and whether the microglial cell type response was improved by targeting the metabolism. We uncovered that LPS, a proinflammatory stimulation of PAMPs, modified the morphology from irregular to fusiform, with stronger cell viability, fusion rates and phagocytosis in the microglia accompanied by a metabolic shift to the promotion of glycolysis and the inhibition of oxidative phosphorylation (OXPHOS). Aβ and ATP, which are two known kinds of DAMPs that trigger microglial sterile activation, induced the morphology from irregular to amoebic, and significantly decreased others in the microglia, accompanied by boosting or reducing both glycolysis and OXPHOS. Monotonous pathological changes and energetic metabolism of microglia were observed under IL-4 exposure. Further, the inhibition of glycolysis transformed the LPS-induced proinflammatory morphology and decreased the enhancement of LPS-induced cell viability, the fusion rate and phagocytosis. However, the promotion of glycolysis exerted a minimal effect on the changes of morphology, the fusion rate, cell viability and phagocytosis induced by ATP. Our study reveals that microglia induced diverse pathological changes accompanied by various changes in the energetic metabolism in response to PAMPs, DAMPs and cytokines, and it may be a potential application of targeting the cellular metabolism to interfere with the microglia-mediated pathological changes in AD.

Increased central auditory gain in 5xFAD Alzheimer's disease mice as an early biomarker candidate for Alzheimer's disease diagnosis.

Alzheimer's Disease (AD) is a neurodegenerative illness without a cure. All current therapies require an accurate diagnosis and staging of AD to ensure appropriate care. Central auditory processing disorders (CAPDs) and hearing loss have been associated with AD, and may precede the onset of Alzheimer's dementia. Therefore, CAPD is a possible biomarker candidate for AD diagnosis. However, little is known about how CAPD and AD pathological changes are correlated. In the present study, we investigated auditory changes in AD using transgenic amyloidosis mouse models. AD mouse models were bred to a mouse strain commonly used for auditory experiments, to compensate for the recessive accelerated hearing loss on the parent background. Auditory brainstem response (ABR) recordings revealed significant hearing loss, a reduced ABR wave I amplitude, and increased central gain in 5xFAD mice. In comparison, these effects were milder or reversed in APP/PS1 mice. Longitudinal analyses revealed that in 5xFAD mice, central gain increase preceded ABR wave I amplitude reduction and hearing loss, suggesting that it may originate from lesions in the central nervous system rather than the peripheral loss. Pharmacologically facilitating cholinergic signaling with donepezil reversed the central gain in 5xFAD mice. After the central gain increased, aging 5xFAD mice developed deficits for hearing sound pips in the presence of noise, consistent with CAPD-like symptoms of AD patients. Histological analysis revealed that amyloid plaques were deposited in the auditory cortex of both mouse strains. However, in 5xFAD but not APP/PS1 mice, plaque was observed in the upper auditory brainstem, specifically the inferior colliculus (IC) and the medial geniculate body (MGB). This plaque distribution parallels histological findings from human subjects with AD and correlates in age with central gain increase. Overall, we conclude that auditory alterations in amyloidosis mouse models correlate with amyloid deposits in the auditory brainstem and may be reversed initially through enhanced cholinergic signaling. The alteration of ABR recording related to the increase in central gain prior to AD-related hearing disorders suggests that it could potentially be used as an early biomarker of AD diagnosis.

Microbiota-gut-brain axis and related therapeutics in Alzheimer's disease: prospects for multitherapy and inflammation control.

Alzheimer's disease (AD) is the most common type of dementia in the elderly and causes neurodegeneration, leading to memory loss, behavioral disorder, and psychiatric impairment. One potential mechanism contributing to the pathogenesis of AD may be the imbalance in gut microbiota, local and systemic inflammation, and dysregulation of the microbiota-gut-brain axis (MGBA). Most of the AD drugs approved for clinical use today are symptomatic treatments that do notimprove AD pathologic changes. As a result, researchers are exploring novel therapeutic modalities. Treatments involving the MGBA include antibiotics, probiotics, transplantation of fecal microbiota, botanical products, and others. However, single-treatment modalities are not as effective as expected, and a combination therapy is gaining momentum. The purpose ofthis review is to summarize recent advances in MGBA-related pathological mechanisms and treatment modalities in AD and to propose a new concept of combination therapy. "MGBA-based multitherapy" is an emerging view of treatment in which classic symptomatic treatments and MGBA-based therapeutic modalities are used in combination. Donepezil and memantine are two commonly used drugs in AD treatment. On the basis of the single/combined use of these two drugs, two/more additional drugs and treatment modalities that target the MGBA are chosen based on the characteristics of the patient's condition as an adjuvant treatment, as well as the maintenance of good lifestyle habits. "MGBA-based multitherapy" offers new insights for the treatment of cognitive impairment in AD patients and is expected to show good therapeutic results.

Degradation of NLRP3 by p62-dependent-autophagy improves cognitive function in Alzheimer's disease by maintaining the phagocytic function of microglia.

Activation of the NLRP3 inflammasome promotes microglia to secrete inflammatory cytokines and induce pyroptosis, leading to impaired phagocytic and clearance functions of microglia in Alzheimer's disease (AD). This study found that the autophagy-associated protein p62 interacts with NLRP3, which is the rate-limiting protein of the NLRP3 inflammasome. Thus, we aimed to prove that the degradation of NLRP3 occurs through the autophagy-lysosome pathway (ALP) and also demonstrate its effects on the function of microglia and pathological changes in AD. The 5XFAD/NLRP3-KO mouse model was established to study the effect of NLRP3 reduction on AD. Behavioral experiments were conducted to assess the cognitive function of the mice. In addition, immunohistochemistry was used to evaluate the deposition of Aβ plaques and morphological changes in microglia. BV2 cells treated with lipopolysaccharide (LPS) followed by Aβ1-42 oligomers were used as in vitro AD inflammation models and transfected with lentivirus to regulate the expression of the target protein. The pro-inflammatory status and function of BV2 cells were detected by flow cytometry and immunofluorescence (IF). Co-immunoprecipitation, mass spectrometry, IF, Western blot (WB), quantitative real-time PCR, and RNA-seq analysis were used to elucidate the mechanisms of molecular regulation. Cognitive function was improved in the 5XFAD/NLRP3-KO mouse model by reducing the pro-inflammatory response of microglia and maintaining the phagocytic and clearance function of microglia to the deposited Aβ plaque. The pro-inflammatory function and pyroptosis of microglia were regulated by NLRP3 expression. Ubiquitinated NLRP3 can be recognized by p62 and degraded by ALP, slowing down the proinflammatory function and pyroptosis of microglia. The expression of autophagy pathway-related proteins such as LC3B/A, p62 was increased in the AD model in vitro. P62 recognizes and binds to ubiquitin-modified NLRP3. It plays a vital role in regulating the inflammatory response by participating in ALP-associated NLRP3 protein degradation, which improves cognitive function in AD by reducing the pro-inflammatory status and pyroptosis of microglia, thus maintaining its phagocytic function.

APOE differentially moderates cerebrospinal fluid and plasma phosphorylated tau181 associations with multi-domain cognition

Biofluid markers of phosphorylated tau181 (p-tau181) are increasingly popular for the detection of early Alzheimer's pathologic changes. However, the differential dynamics of cerebrospinal fluid (CSF) and plasma p-tau181 remain under investigation. We studied 727 participants from the Alzheimer's Disease Neuroimaging Initiative with plasma and CSF p-tau181 data, apolipoprotein (APOE) ε4 carrier status, amyloid positron emission tomography (PET) imaging, and neuropsychological data. Higher levels of plasma and CSF p-tau181 were observed among APOE ε4 carriers. CSF and plasma p-tau181 were significantly associated with memory, and this effect was greater in APOE ε4 carriers. However, whereas CSF p-tau181 was not significantly associated with language or attention/executive function among ε4 carriers or non-carriers, APOE ε4 status moderated the association of plasma p-tau181 with both language and attention/executive function. These findings lend support to the notion that p-tau181 biofluid markers are useful in measuring AD pathologic changes but also suggest that CSF and plasma p-tau181 have unique properties and dynamics that should be considered when using these markers in research and clinical practice.

The Alzheimer's Association Appropriate Use Recommendations for Blood Biomarkers in Alzheimer’s Disease

AbstractBackgroundBlood‐based markers (BBMs) have recently showed promise to revolutionize the diagnostic and prognostic work‐up of Alzheimer's disease (AD), as well as to improve the design of interventional trials.MethodHere we discuss in detail further research needed to be performed before widespread use of BBMs.ResultWe already now recommend use of BBMs as (pre‐)screeners to identify individuals likely to have AD pathological changes for inclusion in trials evaluating disease‐modifying therapies, provided the AD status is confirmed with positron emission tomography (PET) or cerebrospinal fluid (CSF) testing. We also encourage studying longitudinal BBM changes in ongoing as well as future interventional trials. However, BBMs should not yet be used as primary endpoints in pivotal trials. Further, we recommend to cautiously start using BBMs in specialized memory clinics as part of the diagnostic work‐up of patients with cognitive symptoms and the results should be confirmed whenever possible with CSF or PET. Additional data are needed before use of BBMs as stand‐alone diagnostic AD markers, or before considering use in primary care.ConclusionWe recommend use of AD‐associated BBMs as (pre‐)screeners in trials and cautious introduction of BBMs in clinical practice, provided AD status in confirmed whenever possible using CSF or PET. We summarize prioritized research needed to be performed before widespread use of AD‐associated BBMs in clinical trials and practice, including different types of preanalytical, analytical and real‐world clinical studies.

The Alzheimer's Association appropriate use recommendations for blood biomarkers in Alzheimer's disease.

Blood-based markers (BBMs) have recently shown promise to revolutionize the diagnostic and prognostic work-up of Alzheimer's disease (AD), as well as to improve the design of interventional trials. Here we discuss in detail further research needed to be performed before widespread use of BBMs. We already now recommend use of BBMs as (pre-)screeners to identify individuals likely to have AD pathological changes for inclusion in trials evaluating disease-modifying therapies, provided the AD status is confirmed with positron emission tomography (PET) or cerebrospinal fluid (CSF) testing. We also encourage studying longitudinal BBM changes in ongoing as well as future interventional trials. However, BBMs should not yet be used as primary endpoints in pivotal trials. Further, we recommend to cautiously start using BBMs in specialized memory clinics as part of the diagnostic work-up of patients with cognitive symptoms and the results should be confirmed whenever possible with CSF or PET. Additional data are needed before use of BBMs as stand-alone diagnostic AD markers, or before considering use in primary care.

Independent APOE4 knock-in mouse models display reduced brain APOE protein, altered neuroinflammation, and simplification of dendritic spines.

APOE is an immunomodulator in the brain and the major genetic risk factor for late-onset Alzheimer's disease (AD). Targeted replacement APOE mice (APOE-TR) have been a useful tool to study the effects of APOE isoforms on brain neurochemistry and activity prior to and during AD. We use newly available APOE knock-in mice (JAX-APOE) to compare phenotypes associated with APOE4 across models. Similar to APOE4-TR mice, JAX-E4 mouse brains showed 27% lower levels of APOE protein compared with JAX-E3 (p < 0.001). We analyzed several neuroinflammatory molecules that have been associated with APOE genotype. SerpinA3 was much higher in APOE4-TR mice to APOE3-TR mice, but this effect was not seen in JAX-APOE mice. There were higher levels of IL-3 in JAX-E4 brains compared with JAX-E3, but other neuroinflammatory markers (IL6, TNFα) were not affected by APOE genotype. In terms of neuronal structure, basal dendritic spine density in the entorhinal cortex was 39% lower in JAX-E4 mice compared with JAX-E3 mice (p < 0.001), again similar to APOE-TR mice. One-week treatment with ibuprofen significantly increased dendritic spine density in the JAX-E4 mice, consistent with our previous finding in APOE-TR mice. Behaviorally, there was no effect of APOE genotype on Barnes Maze learning and memory in 6-month-old JAX-APOE mice. Overall, the experiments performed in JAX-APOE mice validated findings from APOE-TR mice, identifying particularly strong effects of APOE4 genotype on lower APOE protein levels and simplified neuron structure. These data demonstrate pathways that could promote susceptibility of APOE4 brains to AD pathological changes.

Role of circRNA in pathogenesis of Alzheimer's disease.

Circular RNA (circRNA) is a covalently closed-loop non-coding RNA that exists widely in the transcriptome of eukaryotic cells. It participates in a variety of pathophysiological processes by acting as a microRNA sponge, regulating the level of protein transcription, and interacting with RNA binding proteins. CircRNA is enriched in the cortex, hippocampus, brain white matter, and photoreceptor neurons of aging bodies, and they can be used as a biomarker for neural senescence. The expression levels of circRNA in peripheral blood and synapses in Alzheimer's disease (AD) patients are increased, which are involved in the occurrence and prognosis of AD. Different circRNAs such as HDAC9, Homer1, Cwc27, Tulp4, and PTK2 can lead to AD pathological changes via increasing amyloid-β deposition, promoting tau protein hyperphosphorylation, aggravating neuroinflammation and mitochondrial dysfunction, which result in the cognitive decline.

Association of plasma biomarkers of amyloid and neurodegeneration with cerebrovascular disease and Alzheimer's disease

The objective of this study was to determine the differential mapping of plasma biomarkers to postmortem neuropathology measures. We identified 64 participants in a population-based study with antemortem plasma markers (amyloid-β [Aβ] x-42, Aβx-40, neurofilament light [NfL], and total tau [T-tau]) who also had neuropathologic assessments of Alzheimer's and cerebrovascular pathology. We conducted weighted linear-regression models to evaluate relationships between plasma measures and neuropathology. Higher plasma NfL and Aβ42/40 ratio were associated with cerebrovascular neuropathologic scales (p < 0.05) but not with Braak stage, neuritic plaque score, or Thal phase. Plasma Aβ42/40 and NfL explained up to 18% of the variability in cerebrovascular neuropathologic scales. In participants predominantly with modest levels of Alzheimer's pathologic change, biomarkers of amyloid and neurodegeneration were associated with cerebrovascular neuropathology. NfL is a non-specific marker of brain injury, therefore its association with cerebrovascular neuropathology was expected. The association between elevated Aβ42/40 and cerebrovascular disease pathology needs further investigation but could be due to the use of less specific amyloid-β assays (x-40, x-42).

Silibinin Ameliorates Formaldehyde-Induced Cognitive Impairment by Inhibiting Oxidative Stress.

Silibinin is a flavonoid extracted from the medicinal plant Silybum marianum (milk thistle), traditionally used to treat liver disease. Recent studies have shown that the antioxidative stress and anti-inflammatory effects of milk thistle are used in the treatment of neurological diseases. Silibinin has antioxidative stress and antiapoptotic effects and reduces cognitive impairment in models of Alzheimer's disease (AD). However, the underlying mechanism of silibinin related to improvement of cognition remains poorly understood. In this study, we used the model of lateral ventricle injection of formaldehyde to examine the related mechanism of silibinin in improving cognitive impairment disorders. Oral administration of silibinin for three weeks significantly attenuated the cognitive deficits of formaldehyde-induced mice in a Y-maze test and Morris water maze test. Y-maze results show that silibinin increases the rate of spontaneous response alternation in FA-induced mice. Silibinin increases the target quadrant spending time and decreases escape latency in the Morris water maze test. We examined the effect of silibinin on the NRF2 signaling pathway, and silibinin promoted the nuclear transfer of NRF2 and increased the expression of HO-1 but did not significantly increase the protein expression of NRF2 in the hippocampus. Well, silibinin reduces the content of DHE and decreases the levels of apoptosis of mature neuron cells. We investigated the effect of silibinin on the content of formaldehyde degrading enzymes; biochemical analyses revealed that silibinin increased GSH and ALDH2 in formaldehyde-induced mice. In addition, as one of the pathological changes of AD, TAU protein is also hyperphosphorylated in FA model mice. Silibinin inhibits the expression of GSK-3β in model mice, thereby reducing the phosphorylation of TAU proteins ser396 and ser404 mediated by GSK3β. Based on our findings, we verified that the mechanism of silibinin improving cognitive impairment may be antioxidative stress, and silibinin is one of the potentially promising drugs to prevent formaldehyde-induced cognitive impairment.

Neuropathologic Findings in Elderly HIV-Positive Individuals.

The elderly HIV-positive population is growing due to the widespread use of combination antiretroviral therapy (cART), but the effects of longstanding HIV infection on brain aging are unknown. A significant proportion of HIV-positive individuals develop HIV-associated neurocognitive disorder (HAND) even on cART, but the pathogenesis of HAND is unknown. Although neuroinflammation is postulated to play an important role in aging and neurodegenerative diseases such as Alzheimer disease (AD), it is unclear whether HIV accelerates aging or increases the risk for AD. We examined the brains of 9 elderly HIV-positive subjects on cART without co-infection by hepatitis C virus compared to 7 elderly HIV-negative subjects. Microglial and astrocyte activation and AD pathologic change in association with systemic comorbidities and neurocognitive assessment were evaluated. There was no difference in microglial or astrocyte activation between our HIV-positive and HIV-negative cohorts. One HIV-positive subject and 2 HIV-negative subjects demonstrated significant amyloid deposition, predominantly in the form of diffuse senile plaques, but these individuals were cognitively normal. Neurofibrillary tangles were sparse in the HIV-positive cohort. There was a high prevalence of cardiovascular comorbidities in all subjects. These findings suggest that multiple factors likely contribute to aging and cognitive impairment in elderly HIV-positive individuals on cART.

Alzheimer Disease.

Alzheimer disease (AD) is the most common cause of dementia in adults (mid to late life), highlighting the importance of understanding the risk factors, clinical manifestations, and recent developments in diagnostic testing and therapeutics. Advances in fluid (CSF and blood-based) and imaging biomarkers are allowing for a more precise and earlier diagnosis of AD (relative to non-AD dementias) across the disease spectrum and in patients with atypical clinical features. Specifically, tau- and amyloid-related AD pathologic changes can now be measured by CSF, plasma, and positron emission tomography (PET) with good precision. Additionally, a better understanding of risk factors for AD has highlighted the need for clinicians to address comorbidities to maximize prevention of cognitive decline in those at risk or to slow decline in patients who are symptomatic. Recent clinical trials of amyloid-lowering drugs have provided not only some optimism that amyloid reduction or prevention may be beneficial but also a recognition that addressing additional targets will be necessary for significant disease modification. Recent developments in fluid and imaging biomarkers have led to the improved understanding of AD as a chronic condition with a protracted presymptomatic phase followed by the clinical stage traditionally recognized by neurologists. As clinical trials of potential disease-modifying therapies continue, important developments in the understanding of the disease will improve clinical care now and lead to more effective therapies in the near future.

The association of enlarged perivascular space with microglia-related inflammation and Alzheimer's pathology in cognitively normal elderly

BackgroundGlymphatic dysfunction may contribute to the accumulation of Alzheimer's disease (AD) pathologies. Conversely, AD pathologic change might also cause neuroinflammation and aggravate glymphatic dysfunction, forming a loop that accelerates AD progression. In vivo validations are needed to confirm their relationships. MethodsIn this study, we included 144 cognitively normal participants with AD pathological biomarker data (baseline CSF Aβ1–42, T-Tau, P-Tau181; plasma P-Tau181 at baseline and at least one follow-up) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Each subject had completed structural MRI scans. Among them, 117 subjects have available neuroinflammatory biomarker (soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and 123 subjects have completed two times [18F]-florbetapir PET. The enlarged PVS (EPVS) visual rating scores in basal ganglia (BG) and centrum semiovale (CS) were assessed on T1-weighted images to reflect glymphatic dysfunction. Intracranial volume and white matter hyperintensities (WMH) volume were also calculated for further analysis. We performed stepwise linear regression models and mediation analyses to estimate the association between EPVS severity, sTREM2, and AD biomarkers. ResultsCS-EPVS degree was associated with CSF sTREM2, annual change of plasma P-tau181 and total WMH volume, whereas BG-EPVS severity was associated with age, gender and intracranial volume. The sTREM2 mediated the association between CSF P-tau181 and CS-EPVS. ConclusionImpaired glymphatic dysfunction could contribute to the accumulation of pathological tau protein. The association between tauopathy and glymphatic dysfunction was mediated by the microglia inflammatory process. These findings may provide evidence for novel treatment strategies of anti-neuroinflammation therapy in the early stage.

Research progress on lncRNAs in Alzheimer's disease.

Alzheimer's disease (AD) is the common neurodegenerative disease in the center never system and the typical dementia in old people. The major pathological changes of AD are the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tangles, loss of cholinergic neurons, inflammation and metabolism dysfunction. However, the molecular mechanism leading to AD pathogenesis is not clear. More and more studies reported that long non-coding RNAs (lncRNAs) play important roles in AD. In this review, we briefly introduce the recent research progress on lncRNAs in AD, including their regulation of clearance of the Aβ plaques, synaptic function, inflammation reaction and mitochondrial function, and thus providing the references for that lncRNAs can serve as a potential diagnostic biomarker and therapeutic target in AD.