Amyloid Plaque Deposition Research Articles

White Matter Hyperintensity and PET‐Based Amyloid Load Correlations: A Meta‐Analysis

AbstractBackgroundWhite matter hyperintensities (WMHs) are prevalent vascular pathologies that often co‐occur with amyloid plaque deposition in Alzheimer’s disease (AD). Previous research has shown that antemortem WMHs correlate well with post‐mortem findings of cerebral amyloid angiopathy (CAA). PET‐amyloid imaging is widely used to assess in‐vivo amyloid load, however the extent to which CAA‐binding of amyloid tracers contributes to global measures of amyloid load is unclear. The aim of this meta‐analysis was to determine the strength of the correlation between amyloid load and WMHs in AD subjects.MethodThirteen studies that reported either a correlation or regression coefficient between amyloid load and WMHs were included. Age, education level, sample size, correlation, study setting (community, clinic, Alzheimer’s Disease Neuroimaging Initiative [ADNI]), amyloid tracer type (florbetapir vs. Pittsburgh compound B [PiB]), and method of WMH quantification (visual vs. volumetric) were extracted. Random effects results were reported for the main and subgroup analyses. Between‐study heterogeneity was quantified using I2 with 95% confidence intervals.ResultThe overall correlation for amyloid load and WMH load was r=.25, 95% CI[.15, .35], p<.001; I2=80%, 95% CI[66%, 88%]. The combined effect size of community and clinic‐based studies (r =0.30) was larger than that of ADNI studies (r=0.21) and had substantially less heterogeneity (I2=67% vs. I2=86%). Florbetapir had a stronger correlation with WMHs (r=0.28) than PiB (r=0.20), with less heterogeneity (I2=71%, I2=87%). Visual methods of WMH quantification yielded a stronger correlation with amyloid load (r=0.38) than volumetric methods (r=0.20), however between‐study heterogeneity was similar for both methods (I2=80%, I2=82%).ConclusionWMHs correlate significantly with amyloid load, but this relationship is strongly influenced by amyloid tracer type and WMH quantification method. A high level of heterogeneity was noted for ADNI studies which further indicates the impact that methodologic and analytic techniques may have on a study’s findings. Although CAA‐related binding cannot be distinguished from parenchymal binding in amyloid‐PET studies, these results provide a general estimate of CAA’s contribution to PET‐based estimates of global amyloid load.

Granulocyte‐Macrophage Colony‐Stimulating Factor Reduces Two Major Pathological Hallmarks of Alzheimer’s Disease and Astrogliosis in the TgF344‐AD Rat Model

AbstractBackgroundGranulocyte‐macrophage colony‐stimulating factor (GM‐CSF), a hematopoietic growth factor and the innate immune system modulator, has shown therapeutic and neuroprotective effects in animal models of Alzheimer’s disease (AD), Parkinson’s disease, Down syndrome, stroke, and normal aging. Recently, Potter et al. (2021) published the results of a Phase2 clinical trial in mild‐to‐moderate AD subjects showing that recombinant human GM‐CSF (sargramostim) treatment shifted both MMSE scores and plasma biomarkers of neurodegeneration toward normal. Cohen et al. (2013) developed a transgenic rat model (TgF344‐AD) that expresses the Swedish mutant human APP (APPsw) and mutant human presenilin 1 (PSEN1 deltaE9) genes that cause familial AD. In addition to cerebral amyloidosis, neuronal loss, and cognitive deficits, TgF344‐AD rats also show age‐dependent tauopathy including overexpression of phosphorylated tau and neurofibrillary tangle formation, which are not present in mouse models of AD. To evaluate the potential ability of GM‐CSF to reverse and/or prevent the full range of AD pathology, we treated ∼20‐month‐old TgF344‐AD rats with GM‐CSF or saline, and investigated AD pathology in the brain and retina. We also analyzed biomarkers in plasma using MSD and SIMOA neuroinflammation panels.MethodTgF344‐AD rats were injected subcutaneously with GM‐CSF (83.3ug/kg/day; 5days/week) or with saline (200ul/day) for 24 injections total over 32 days. On day 32, blood samples were collected, plasma samples were used for biomarkers assays, and brain and retinal tissues were processed for immunohistochemistry and immunoblotting.ResultTgF344‐AD rats treated with GM‐CSF showed a significant reduction in amyloid plaque deposition in the cortex and a strong trend towards reduced plaque deposition in the hippocampal CA region compared to saline‐treated TgF344‐AD rats. We also observed a trend of reduced phosphorylated tau expression in the cortex and hippocampal region in GM‐CSF‐treated TgF344‐AD rats. In addition, GM‐CSF treatment significantly reduced astrogliosis in the CA1 and dentate gyrus/hilus regions of TgF344‐AD rats.ConclusionAlthough experiments are ongoing, our findings indicate that GM‐CSF treatment rescues two major pathological hallmarks of AD and neuroinflammation (astrogliosis) in TgF344‐AD rats. Our results suggest that GM‐CSF/sargramostim/Leukine® may be a potential therapeutic not only for reducing amyloidosis, but also for reducing levels of hyperphosphorylated tau and other relevant pathological manifestations of AD.

CSF immune activation in Alzheimer’s disease driven by tau‐ and not amyloid pathology

AbstractBackgroundGenetic studies suggest involvement of the immune system in Alzheimer’s disease (AD) development, and neuroinflammation has been suggested as a key driver of AD. We here employ cerebrospinal fluid (CSF) markers to study whether immune‐ and glial activation are primary features of early amyloid plaque deposition, or follow significant tau pathology as the disease progresses.MethodWe included n=267 non‐demented cases with repeated CSF samples (1‐6 years). The presence of amyloid pathology (A), tau‐tangle pathology (T) and neurodegeneration (N) using Aß42/40 ratio, p‐tau181 and total‐tau were determined at baseline and follow‐ups. We then selected participants (n=226) that remained stable A‐/T‐/N‐ (n=134), A+/T‐/N‐ (n=33) and A+/T+/N+ (n=34) over time and cases that progressed from A‐/T‐/N‐ to A+/T‐/N‐ (n=14) and A+/T‐/N‐ to A+/T or N+ (n=11). Other A/T/N categories (e.g. A‐/T or N+) were excluded. Mixed Linear Models (MLMs) were used to measure longitudinal changes in CSF sTREM2, YKL‐40, clusterin, fractalkine, MCP‐1, IFN‐γ, IL‐6, IL‐18 and IL‐10 between groups with stable A‐/T‐/N‐ group as the reference. All models included age, sex and number of APOEε4 alleles as covariates.ResultCompared to stable A‐/T‐/N‐, cases progressing from A‐/T‐/N‐ to A+/T‐/N‐ had lower sTREM2 levels (p=.022) over time, and both fractalkine (p=.053), IFN‐γ (p=.055) and clusterin levels (p=.068) showed trend levels towards lower levels. In stable A+/T‐/N‐ cases, YKL‐40 (p=.007) and fractalkine (p=.043) were lower than stable A‐/T‐/N‐ over time. A+/T+/N+ cases had markedly higher sTREM2, fractalkine and clusterin levels (all p<.001) that remained high over time. In this group the YKL‐40 levels were also higher at baseline (p<.001) and increased slightly over time (p=.032). There were no between‐group differences at neither baseline or over time in the CSF levels of MCP‐1, IL‐6, IL‐18 and IL‐10.ConclusionAmyloid pathology alone was not associated with increased immune and glial activation in our cohort, and several of the CSF immune markers were lower in both those progressing to A+/T‐/N‐ and the stable A+/T‐/N‐. An increase in activation markers was only shown in cases with tau‐pathology at baseline, or in cases that developed tau pathology during the follow‐up period, suggesting immune activation in response to tau pathology.

Sirt3 deficiency induced down regulation of insulin degrading enzyme in comorbid Alzheimer’s disease with metabolic syndrome

SIRT3 deacetylates mitochondrial proteins, thereby enhancing their function. We have previously demonstrated that Sirt3 gene deletion leads to brain mitochondrial dysfunction and neuroinflammation. We also reported that silencing of Sirt3 gene in APP/PS1 mice results in exacerbation of insulin resistance, neuroinflammation and β amyloid plaque deposition. To further understand how metabolic syndrome and amyloid pathology interact, we performed RNA-seq analysis of the brain samples of APP/PS1/Sirt3-/- mice. Gene expression patterns were modulated in metabolic and inflammatory pathways by Sirt3 gene deletion, amyloid pathology, and the combination. Following Sirt3 gene deletion, a key finding was the decreased expression of insulin-degrading enzyme (IDE), an enzyme that regulates the levels of insulin and Aβ peptides. Western diet feeding of Sirt3-/- and APP/PS1 mice resulted in decrease of IDE protein, parallel to Sirt3 downregulation. Conversely, activation of SIRT3 by nicotinamide riboside in vivo and in vitro resulted in IDE upregulation. SIRT3 activation in vivo also increased the levels of neprilysin, another Aβ degrading enzyme and decreased the levels of BACE1 which generates Aβ peptide suggesting SIRT3’s role in amyloid plaque reduction. Our findings provide a plausible mechanism linking metabolic syndrome and amyloid pathology. SIRT3 may be a potential therapeutic target to treat AD.

Mitochondrial Alterations in Neurons Derived from the Murine AppNL-F Knock-In Model of Alzheimer's Disease.

Alzheimer's disease (AD) research has relied on mouse models overexpressing human mutant A βPP; however, newer generation knock-in models allow for physiological expression of amyloid-β protein precursor (AβPP) containing familial AD mutations where murine AβPP is edited with a humanized amyloid-β (Aβ) sequence. The AppNL-F mouse model has shown substantial similarities to AD brains developing late onset cognitive impairment. In this study, we aimed to characterize mature primary cortical neurons derived from homozygous AppNL-F embryos, especially to identify early mitochondrial alterations in this model. Primary cultures of AppNL-F neurons kept in culture for 12-15 days were used to measure Aβ levels, secretase activity, mitochondrial functions, mitochondrial-ER contacts, synaptic function, and cell death. We detected higher levels of Aβ42 released from AppNL-F neurons as compared to wild-type neurons. AppNL-F neurons, also displayed an increased Aβ42/Aβ40 ratio, similar to adult AppNL-F mouse brain. Interestingly, we found an upregulation in mitochondrial oxygen consumption with concomitant downregulation in glycolytic reserve. Furthermore, AppNL-F neurons were more susceptible to cell death triggered by mitochondrial electron transport chain inhibition. Juxtaposition between ER and mitochondria was found to be substantially upregulated, which may account for upregulated mitochondrial-derived ATP production. However, anterograde mitochondrial movement was severely impaired in this model along with loss in synaptic vesicle protein and impairment in pre- and post-synaptic function. We show that widespread mitochondrial alterations can be detected in AppNL-F neurons in vitro, where amyloid plaque deposition does not occur, suggesting soluble and oligomeric Aβ-species being responsible for these alterations.

Accelerated amyloid angiopathy and related vascular alterations in a mixed murine model of Alzheimer´s disease and type two diabetes

BackgroundWhile aging is the main risk factor for Alzheimer´s disease (AD), emerging evidence suggests that metabolic alterations such as type 2 diabetes (T2D) are also major contributors. Indeed, several studies have described a close relationship between AD and T2D with clinical evidence showing that both diseases coexist. A hallmark pathological event in AD is amyloid-β (Aβ) deposition in the brain as either amyloid plaques or around leptomeningeal and cortical arterioles, thus constituting cerebral amyloid angiopathy (CAA). CAA is observed in 85–95% of autopsy cases with AD and it contributes to AD pathology by limiting perivascular drainage of Aβ.MethodsTo further explore these alterations when AD and T2D coexist, we have used in vivo multiphoton microscopy to analyze over time the Aβ deposition in the form of plaques and CAA in a relevant model of AD (APPswe/PS1dE9) combined with T2D (db/db). We have simultaneously assessed the effects of high-fat diet-induced prediabetes in AD mice. Since both plaques and CAA are implicated in oxidative-stress mediated vascular damage in the brain, as well as in the activation of matrix metalloproteinases (MMP), we have also analyzed oxidative stress by Amplex Red oxidation, MMP activity by DQ™ Gelatin, and vascular functionality.ResultsWe found that prediabetes accelerates amyloid plaque and CAA deposition, suggesting that initial metabolic alterations may directly affect AD pathology. T2D significantly affects vascular pathology and CAA deposition, which is increased in AD-T2D mice, suggesting that T2D favors vascular accumulation of Aβ. Moreover, T2D synergistically contributes to increase CAA mediated oxidative stress and MMP activation, affecting red blood cell velocity.ConclusionsOur data support the cross-talk between metabolic disease and Aβ deposition that affects vascular integrity, ultimately contributing to AD pathology and related functional changes in the brain microvasculature.

Thiamine insufficiency induces Hypoxia Inducible Factor-1α as an upstream mediator for neurotoxicity and AD-like pathology

Insufficiencies of the micronutrient thiamine (Vitamin B1) have been associated with inducing Alzheimer's disease (AD)-like neuropathology. The hypometabolic state associated with chronic thiamine insufficiency (TI) has been demonstrated to be a contributor towards the development of amyloid plaque deposition and neurotoxicity. However, the molecular mechanism underlying TI induced AD pathology is still unresolved. Previously, we have established that TI stabilizes the metabolic stress transcriptional factor, Hypoxia Inducible Factor-1α (HIF1α). Utilizing neuronal hippocampal cells (HT22), TI-induced HIF1α activation triggered the amyloidogenic cascade through transcriptional expression and increased activity of β-secretase (BACE1). Knockdown and pharmacological inhibition of HIF1α during TI significantly reduced BACE1 and C-terminal Fragment of 99 amino acids (C99) formation. TI also increased the expression of the HIF1α regulated pro-apoptotic protein, BCL2/adenovirus E1B 19 kDa protein-interacting protein (BNIP3). Correspondingly, cell toxicity during TI conditions was significantly reduced with HIF1α and BNIP3 knockdown. The role of BNIP3 in TI-mediated toxicity was further highlighted by localization of dimeric BNIP3 into the mitochondria and nuclear accumulation of Endonuclease G. Subsequently, TI decreased mitochondrial membrane potential and enhanced chromatin fragmentation. However, cell toxicity via the HIF1α/BNIP3 cascade required TI induced oxidative stress. HIF1α, BACE1 and BNIP3 expression was induced in 3xTg-AD mice after TI and administration with the HIF1α inhibitor YC1 significantly attenuated HIF1α and target genes levels in vivo. Overall, these findings demonstrate a critical stress response during TI involving the induction of HIF1α transcriptional activity that directly promotes neurotoxicity and AD-like pathology.

Early death in a mouse model of Alzheimer’s disease exacerbated by microglial loss of TAM receptor signaling

Recurrent seizure is a common comorbidity in early-stage Alzheimer's disease (AD) and may contribute to AD pathogenesis and cognitive decline. Similarly, many mouse models of Alzheimer's disease that overproduce amyloid beta are prone to epileptiform seizures that may result in early sudden death. We studied one such model, designated APP/PS1, and found that mutation of the TAM receptor tyrosine kinase (RTK) Mer or its ligand Gas6 greatly exacerbated early death. Lethality was tied to violent seizures that appeared to initiate in the dentate gyrus (DG) of the hippocampus, where Mer plays an essential role in the microglial phagocytosis of both apoptotic and newborn cells normally generated during adult neurogenesis. We found that newborn DG neurons and excitatory synapses between the DG and the cornu ammonis field 3 (CA3) field of the hippocampus were increased in TAM-deficient mice, and that premature death and adult neurogenesis in these mice were coincident. In contrast, the incidence of lethal seizures and the deposition of dense-core amyloid plaques were strongly anticorrelated. Together, these results argue that TAM-mediated phagocytosis sculpts synaptic connectivity in the hippocampus, and that seizure-inducing amyloid beta polymers are present prior to the formation of dense-core plaques.

Increased Type I interferon signaling and brain endothelial barrier dysfunction in an experimental model of Alzheimer’s disease

Blood–brain barrier (BBB) dysfunction is emerging as a key pathogenic factor in the progression of Alzheimer’s disease (AD), where increased microvascular endothelial permeability has been proposed to play an important role. However, the molecular mechanisms leading to increased brain microvascular permeability in AD are not fully understood. We studied brain endothelial permeability in female APPswe/PS1∆E9 (APP/PS1) mice which constitute a transgenic mouse model of amyloid-beta (Aβ) amyloidosis and found that permeability increases with aging in the areas showing the greatest amyloid plaque deposition. We performed an unbiased bulk RNA-sequencing analysis of brain endothelial cells (BECs) in female APP/PS1 transgenic mice. We observed that upregulation of interferon signaling gene expression pathways in BECs was among the most prominent transcriptomic signatures in the brain endothelium. Immunofluorescence analysis of isolated BECs from female APP/PS1 mice demonstrated higher levels of the Type I interferon-stimulated gene IFIT2. Immunoblotting of APP/PS1 BECs showed downregulation of the adherens junction protein VE-cadherin. Stimulation of human brain endothelial cells with interferon-β decreased the levels of the adherens junction protein VE-cadherin as well as tight junction proteins Occludin and Claudin-5 and increased barrier leakiness. Depletion of the Type I interferon receptor in human brain endothelial cells prevented interferon-β-induced VE-cadherin downregulation and restored endothelial barrier integrity. Our study suggests that Type I interferon signaling contributes to brain endothelial dysfunction in AD.

Statins Use in Alzheimer Disease: Bane or Boon from Frantic Search and Narrative Review.

Alzheimer’s disease (AD) was used to describe pre-senile dementia to differentiate it from senile dementia, which develops in the adult age group of more than 65 years. AD is characterized by the deposition of amyloid beta (Aβ) plaque and tau-neurofibrillary tangles (TNTs) in the brain. The neuropathological changes in AD are related to the deposition of amyloid plaques, neurofibrillary tangles, and progression of neuroinflammation, neuronal mitochondrial dysfunction, autophagy dysfunction, and cholinergic synaptic dysfunction. Statins are one of the main cornerstone drugs for the management of cardiovascular disorders regardless of dyslipidemia status. Increasing the use of statins, mainly in the elderly groups for primary and secondary prevention of cardiovascular diseases, may affect their cognitive functions. Extensive and prolonged use of statins may affect cognitive functions in healthy subjects and dementia patients. Statins-induced cognitive impairments in both patients and health providers had been reported according to the post-marketing survey. This survey depends mainly on sporadic cases, and no cognitive measures were used. Evidence from prospective and observational studies gives no robust conclusion regarding the beneficial or detrimental effects of statins on cognitive functions in AD patients. Therefore, this study is a narrative review aimed with evidences to the beneficial, detrimental, and neutral effects of statins on AD.

Recall and recognition subtests of the repeatable battery for the assessment of neuropsychological status and their relationship to biomarkers of Alzheimer’s disease

ABSTRACT Recently, two new recognition subtests for the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were developed and initially validated in a cohort of older adults who were cognitively intact or classified as amnestic Mild Cognitive Impairment (MCI) or mild Alzheimer’s disease (AD). The current paper extends that validation by comparing the recall and recognition subtests of the RBANS, including the existing and recently developed scores, to three commonly used biomarkers in AD in an expanded sample from the initial validation. One hundred fifty-four older adults (65 intact, 46 MCI, 43 AD) were administered the RBANS, which included the recently developed subtests for Story Recognition and Figure Recognition (hits, false positives, total correct), as part of a study on memory and biomarkers. Participants also completed magnetic resonance imaging to obtain hippocampal volumes, positron emission tomography to obtain amyloid plaque deposition, and a blood draw to obtain APOE ε4 status. Whereas correlations between recall scores and biomarkers tended to be moderate (average r = ±0.48), these correlations were comparable across the three recognition total scores (average r = ±0.42), but tended to be lower for recognition hits (average r = ±0.28) and false positives (average r = ±0.38). These results further validate the existing and recently developed recognition scores on the RBANS as providing useful information about brain and genetic pathology in older adults with intact and impaired cognitive functioning.

Cognitive Dysfunction and Anxiety Resulting from Synaptic Downscaling, Hippocampal Atrophy, and Ventricular Enlargement with Intracerebroventricular Streptozotocin Injection in Male Wistar Rats.

Insulin-resistant brain state is proposed to be the early sign of Alzheimer's disease (AD), which can be studied in the intracerebroventricular streptozotocin (ICV-STZ) rodent model. ICV-STZ is reported to induce sporadic AD with the majority of the disease hallmarks as phenotype. On the other hand, available experimental evidence has used varying doses of STZ (< 1 to 3mg/kg) and studied its effect for different study durations, ranging from 14 to 270days. Though these studies suggest 3mg/kg of ICV-STZ to be the optimum dose for progressive pathogenesis, the reason for such is elusive.Here, we sought to investigate the mechanism of action of 3mg/kg ICV-STZ on cognitive and non-cognitive aspects at a follow-up interval of 2weeks for 2months. On the 60th day, we examined the layer thickness, cell density, ventricular volume, spine density, protein expression related to brain metabolism, and mitochondrial function by histological examination. The findings suggest a progressive loss of a spatial, episodic, and avoidance memory with an increase in anxiety in a span of 2months. Furthermore, hippocampal neurodegeneration, ventricular enlargement, diffused amyloid plaque deposition, loss of spine in the dentate gyrus, and imbalance in energy homeostasis were found on the 60th day post-injection. Interestingly, AD rats showed a uniform fraction of time spent in four quadrants of the water maze with a change in strategy when they were exposed to height. Our findings reveal that ICV-STZ injection at a dose of 3mg/kg can cause cognitive and neuropsychiatric abnormalities due to structural loss both at the neuronal as well as the synaptic level, which is tightly associated with the change in neuronal metabolism.

Dracaena cochinchinensis stemwood extracts inhibit amyloid-β fibril formation and promote neuronal cell differentiation.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the deposition of amyloid plaques in the brain. The prevention of amyloid-β (Aβ)-induced neuronal toxicity is considered a major target for drug development for AD treatment. Dracaena cochinchinensis (Lour.) S.C. Chen, a Thai folk medicine named “Chan-Daeng,” is a member of the Asparagaceae family. The stemwood of D. cochinchinensis has been traditionally used for its antipyretic, pain relief, and anti-inflammatory effects. The aim of the present study was to determine the pharmacological activities of ethanol and water extracts of D. cochinchinensis stemwood in blocking the Aβ fibril formation, preventing Aβ-mediated cell toxicity, and promoting neuronal differentiation in cultured PC12 cells. The herbal extracts of D. cochinchinensis stemwood prevented the formation of Aβ fibrils and disassembled the aggregated Aβ in a dose-dependent manner. Additionally, they prevented Aβ fibril-mediated cell death. The synergy of the herbal extract with a low dose of the nerve growth factor showed an increase in the protein expression of neurofilaments, that is, NF68, NF160, and NF200. These findings suggest that the extracts of D. cochinchinensis stemwood may be used for AD treatment by targeting Aβ fibril formation and inducing neuron regeneration.

Resetting the circadian clock of Alzheimer's mice via GLP-1 injection combined with time-restricted feeding.

Circadian rhythm disturbances are the most common symptoms during the early onset of AD. Circadian rhythm disorders aggravate the deposition of amyloid plaques in the brains of AD patients. Therefore, improving the circadian rhythm of AD patients might slow down the pathological development of neurodegeneration. Circadian regulation is driven by a master clock in suprachiasmatic nuclei (SCN) and peripheral clock located in peripheral organs. The rhythmic feeding–fasting cycle has been proved to dominant cue to entrain peripheral clocks. We hypothesized that dietary intervention to a certain period of time during the dark phase might entrain the clock and reset the disrupted daily rhythms of AD mice. In this study, exogenous glucagon-like peptide-1 (GLP-1) treatment, time-restricted feeding (TRF), and the combination were used to examine the effect of overall circadian rhythm and neurodegenerative pathogenesis of transgenic AD mice. It was confirmed that GLP-1 administration together with time-restricted feeding improves circadian rhythm of 5 × FAD mice including the physiological rhythm of the activity–rest cycle, feeding–fasting cycle, core body temperature, and hormone secretion. Furthermore, GLP-1 and TRF treatments improved the diurnal metabolic homeostasis, spatial cognition, and learning of 5 × FAD mice. The aberrant expression of clock genes, including Baml1, Clock, and Dbp, was improved in the hypothalamus, and pathological changes in neurodegeneration and neuroinflammation were also observed in AD mice with dual treatment.

Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer's disease.

SummaryDysfunctions of network activity and functional connectivity (FC) represent early events in Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. Astrocytes regulate local neuronal activity in the healthy brain, but their involvement in early network hyperactivity in AD is unknown. We show increased FC in the human cingulate cortex several years before amyloid deposition. We find the same early cingulate FC disruption and neuronal hyperactivity in AppNL-F mice. Crucially, these network disruptions are accompanied by decreased astrocyte calcium signaling. Recovery of astrocytic calcium activity normalizes neuronal hyperactivity and FC, as well as seizure susceptibility and day/night behavioral disruptions. In conclusion, we show that astrocytes mediate initial features of AD and drive clinically relevant phenotypes.

Early loss of locus coeruleus innervation promotes cognitive and neuropathological changes before amyloid plaque deposition in a transgenic rat model of Alzheimer's disease.

The locus coeruleus (LC) is the main source of noradrenaline (NA) in the mammalian brain and has been found to degenerate during the initial stages of Alzheimer's disease (AD). Recent studies indicate that at late stages of the amyloid pathology, LC-pathological alterations accelerate AD-like pathology progression by interfering with the neuromodulatory and anti-inflammatory properties of NA. However, the impact of LC degeneration at the earliest stages of amyloidosis on the AD-like pathology is not well understood. The LC was lesioned in wild-type and McGill-R-Thy1-APP transgenic (APP tg) rats by administering N-(2-chloroethyl)-N-ethyl-bromo-benzylamine before amyloid plaque deposition. Cognitive deficits and AD-like neuropathological changes were measured after the LC lesion. Four months post-treatment, rats displayed a decrease in brain noradrenergic innervation. The LC lesion in APP tg-treated rats enhanced cognitive deficits and decreased hippocampal cholinergic innervation and neurotrophin expression. In addition, the APP tg-treated rats displayed an increased microglial and astroglial cell number in close vicinity to hippocampal amyloid-beta burdened neurons. The recruited microglia showed cellular alterations indicative of an intermediate activation state. Our results indicate that early LC demise aggravates the early neuroinflammatory process, cognitive impairments, cholinergic deficits and neurotrophin deregulation at the earliest stages of the human-like brain amyloidosis.

Novel Alzheimer risk factor IQ motif containing protein K is abundantly expressed in the brain and is markedly increased in patients with Alzheimer’s disease

Alzheimer’s disease (AD) is complex and highly heterogeneous. Less than 10% of AD cases are early-onset (EOAD) caused by autosomal dominantly inherited mutations in amyloid precursor protein (APP), presenilin 1 (PS1), or presenilin 2 (PS2), each of which can increase Aβ generation and, thus, amyloid plaques. The remaining 90% of cases of AD are late-onset (LOAD) or sporadic. Intense research efforts have led to identification of many genes that increase the risk of AD. An IQ motif containing protein K (IQCK) was recently identified by several investigators as an Alzheimer’s disease risk gene. However, how IQCK increases AD risk is completely unknown. Since IQCK is a novel gene, there is limited information on its physiological characterization. To understand its role in AD, it is first important to determine its subcellular localization, whether and where it is expressed in the brain, and what type of brain cells express the IQCK protein. Therefore, in this study, we show by immunocytochemical (ICC) staining that IQCK is expressed in both the nucleus and the cytoplasm of SH-SY5Y neuroblastoma cells as well as HeLa cells but not in either HMC3 microglial or CHO cells. By immunohistochemistry (IHC), we also show that IQCK is expressed in both mouse and human neurons, including neuronal processes in vivo in the mouse brain. IHC data also show that the IQCK protein is widely expressed throughout the mouse brain, although regional differences were noted. IQCK expression was highest in the brainstem (BS), followed by the cerebellum (CB) and the cortex (CX), and it was lowest in the hippocampus (HP). This finding was consistent with data from an immunoblot analysis of brain tissue homogenates. Interestingly, we found IQCK expression in neurons, astrocytes, and oligodendrocytes using cell-specific antibodies, but IQCK was not detected in microglial cells, consistent with negative in vitro results in HMC3 cells. Most importantly, we found that actin-normalized IQCK protein levels were increased by 2 folds in AD brains relative to normal control (NC) brains. Furthermore, the IQCK protein was found in amyloid plaques, suggesting that IQCK may play a pathogenic role in either Aβ generation or amyloid plaque deposition in AD.

Intraneuronal β-Amyloid Accumulation: Aging HIV-1 Human and HIV-1 Transgenic Rat Brain.

The prevalence of HIV-1 associated neurocognitive disorders (HAND) is significantly greater in older, relative to younger, HIV-1 seropositive individuals; the neural pathogenesis of HAND in older HIV-1 seropositive individuals, however, remains elusive. To address this knowledge gap, abnormal protein aggregates (i.e., β-amyloid) were investigated in the brains of aging (>12 months of age) HIV-1 transgenic (Tg) rats. In aging HIV-1 Tg rats, double immunohistochemistry staining revealed abnormal intraneuronal β-amyloid accumulation in the prefrontal cortex (PFC) and hippocampus, relative to F344/N control rats. Notably, in HIV-1 Tg animals, increased β-amyloid accumulation occurred in the absence of any genotypic changes in amyloid precursor protein (APP). Furthermore, no clear amyloid plaque deposition was observed in HIV-1 Tg animals. Critically, β-amyloid was co-localized with neurons in the cortex and hippocampus, supporting a potential mechanism underlying synaptic dysfunction in the HIV-1 Tg rat. Consistent with these neuropathological findings, HIV-1 Tg rats exhibited prominent alterations in the progression of temporal processing relative to control animals; temporal processing relies, at least in part, on the integrity of the PFC and hippocampus. In addition, in post-mortem HIV-1 seropositive individuals with HAND, intraneuronal β-amyloid accumulation was observed in the dorsolateral PFC and hippocampal dentate gyrus. Consistent with observations in the HIV-1 Tg rat, no amyloid plaques were found in these post-mortem HIV-1 seropositive individuals with HAND. Collectively, intraneuronal β-amyloid aggregation observed in the PFC and hippocampus of HIV-1 Tg rats supports a potential factor underlying HIV-1 associated synaptodendritic damage. Further, the HIV-1 Tg rat provides a biological system to model HAND in older HIV-1 seropositive individuals.

Insights of Valacyclovir in Treatment of Alzheimer's Disease: Computational Docking Studies and Scopolamine Rat Model.

Alzheimer's Disease (AD) impairs memory and cognitive functions in the geriatric population and is characterized by intracellular deposition of neurofibrillary tangles, extracellular deposition of amyloid plaques, and neuronal degeneration. Literature suggests that latent viral infections in the brain act as prions and promote neurodegeneration. Memantine possesses both anti-viral and N-methyl-D-aspartate (NMDA) receptor antagonistic activity. This research was designed to evaluate the efficacy of antiviral agents, especially valacyclovir, a prodrug of acyclovir in ameliorating the pathology of AD based on the presumption that anti-viral agents targeting the Herpes Simplex Virus (HSV) can have a protective effect on neurodegenerative diseases like Alzheimer's disease. Thus, we evaluated acyclovir's potential activity by in-silico computational docking studies against acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and beta-secretase 1 (BACE-1). These findings were further evaluated by in-vivo scopolamine-induced cognitive impairment in rats. Two doses of valacyclovir, a prodrug of acyclovir (100 mg/kg and 150 mg/kg orally) were tested. Genetic Optimisation for Ligand Docking scores and fitness scores of acyclovir were comparable to donepezil. Valacyclovir improved neurobehavioral markers. It inhibited AChE and BuChE (p<0.001) enzymes. It also possessed disease-modifying efficacy as it decreased the levels of BACE-1 (p<0.001), amyloid beta 1-42 (p<0.001), amyloid beta 1-40 (p<0.001), phosphorylatedtau (p<0.001), neprilysin (p<0.01), and insulin-degrading enzyme. It ameliorated neuroinflammation through decreased levels of tumour necrosis factor α (p<0.001), nuclear factor-kappa B (p<0.001), interleukin 6 (p<0.001), interleukin 1 beta (p<0.001), and interferon-gamma (p<0.001). It also maintained synaptic plasticity and consolidated memory. Histopathology showed that valacyclovir could restore cellular density and also preserve the dentate gyrus. Valacyclovir showed comparable activity to donepezil and thus can be further researched for the treatment of Alzheimer's disease.

The impact of gamma-radiation on the cerebral- and cerebellar- cortex of male rats’ brain

This study aims to investigate the impact of gamma-radiation on the cerebral- and cerebellar-cortex of rat’s brain. Animals were whole-body exposed to 3 Gy, every 3 days, up to 9 Gy, and sacrificed 1 h, 1, 3, 7 & 10 days post the last radiation-dose. Irradiation triggers oxidative stress. Superoxide dismutase, catalase, glutathione reductase decreased, malondialdehyde and protein carbonyl increased from the 1st hour till the 10th day in both tissues. Glutathione peroxidase and glutathione decreased from the 1st hour in the cerebral-cortex, and 3rd day in the cerebellar-cortex. Irradiation increased the inflammatory marker, tumor necrosis factor-alpha, and the apoptotic markers, cytochrome-c and caspase-3 from the 1st hour till the 10th day in both tissues. β-amyloid was observed the 7th and 10th day in cerebral-cortex and 3rd, 7th and 10th day in cerebellar-cortex. Irradiation change the level of neurotransmitters. Norepinephrine decreased from the 1st hour in both tissues, while dopamine, epinephrine, aspartic acid, glutamic acid decreased, and gamma amino butyric acid increased from the 1st hour in the cerebral-cortex and later on the 3rd day in the cerebellar-cortex. Electroencephalographic measurement (EEG) showed significant decreases in the frequencies of beta-(>12 Hz) alpha-(7–12 Hz), theta-(4–7 Hz), and delta-rhythms (1–4 Hz) from the 1st hour in both occipital and parietal areas of the brain. Gamma-irradiation triggers oxidative stress, change the level of neurotransmitters, increase inflammatory and apoptotic responses, enhance deposition of amyloid plaque in the cerebral- and cerebellar- cortex, and decrease brain electrical activity in occipital and parietal areas of the brain.