Dysfunction In Alzheimer's Disease Research Articles

Noradrenergic Add-on Therapy with Extended-Release Guanfacine in Alzheimer’s Disease (NorAD): study protocol for a randomised clinical trial and COVID-19 amendments

BackgroundGuanfacine is a α2A adrenergic receptor agonist approved for treating attention deficit hyperactivity disorder (ADHD). It is thought to act via postsynaptic receptors in the prefrontal cortex, modulating executive functions including the regulation of attention. Attention is affected early in Alzheimer’s disease (AD), and this may relate to pathological changes within the locus coeruleus, the main source of noradrenergic pathways within the brain. Given that cholinergic pathways, also involved in attention, are disrupted in AD, the combination of noradrenergic and cholinergic treatments may have a synergistic effect on symptomatic AD. The primary objective of the NorAD trial is to evaluate the change in cognition with 12 weeks of treatment of extended-release guanfacine (GXR) against a placebo as a combination therapy with cholinesterase inhibitors in participants with mild to moderate Alzheimer’s disease.Methods/designNorAD is a 3-month, single-centre, randomised, double-blind, placebo-controlled, phase III trial of extended-release guanfacine (GXR) in participants with mild to moderate Alzheimer’s disease. A total of 160 participants will be randomised to receive either daily guanfacine or placebo in combination with approved cholinesterase treatment for 12 weeks. The primary outcome is the change in cognition, as measured by the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), from baseline to follow-up in the treatment group compared to the placebo group. Secondary outcomes include the change in additional cognitive measures of attention (Tests of Attention: Trails A and B, digit-symbol substitution, Test of Everyday Attention and CANTAB-RVP), neuropsychiatric symptoms (Neuropsychiatric Inventory), caregiver burden (Zarit Burden Interview) and activities of daily living (Alzheimer’s Disease Co-operative Study – Activities of Daily Living Inventory). From July 2020, observation of change following cessation of treatment is also being assessed.DiscussionThere is strong evidence for early noradrenergic dysfunction in Alzheimer’s disease. The NorAD trial aims to determine whether guanfacine, a noradrenergic alpha-2 agonist, improves attention and cognition when used in addition to standard cholinergic treatment.Trial registrationClinicalTrials.govNCT03116126. Registered on 14 April 2017EudraCT: 2016-002598-36

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.

Aβ1-42 peptides blunt the adenosine A2A receptor-mediated control of the interplay between P2X7 and P2Y1 receptors mediated calcium responses in astrocytes.

The contribution of astrocytes to Alzheimer's disease (AD) is still ill defined. AD involves an abnormal accumulation of amyloid-β peptides (Aβ) and increased production of danger signals such as ATP. ATP can direct or indirectly, through its metabolism into adenosine, trigger adaptive astrocytic responses resulting from intracellular Ca2+ oscillations. AD also triggers an upregulation of astrocytic adenosine A2A receptors (A2AR), which blockade prevents memory dysfunction in AD. We now investigated how Aβ peptides affect ATP-mediated Ca2+ responses in astrocytes measured by fluorescence live-cell imaging and whether A2AR control astrocytic Ca2+ responses mediated by ATP receptors, mainly P2X7R and P2Y1R. In primary cultures of rat astrocytes exposed to Aβ1-42, ATP-evoked Ca2+ responses had a lower amplitude but a longer duration than in control astrocytes and involved P2X7R and P2Y1R, the former potentiating the later. Moreover, Aβ1-42 exposure increased protein levels of P2Y1R in astrocytes. A2AR antagonism with SCH58261 controlled in a protein kinase A-dependent manner both P2X7R- and P2Y1R-mediated Ca2+ responses in astrocytes. The interplay between these purinoceptors in astrocytes was blunted upon exposure to Aβ1-42. These findings uncover the ability of A2AR to regulate the inter-twinned P2X7R- and P2Y1R-mediated Ca2+ dynamics in astrocytes, which is disrupted in conditions of early AD.

Critical appraisal on mitochondrial dysfunction in Alzheimer's disease.

It is widely recognized that Alzheimer's disease (AD) is a common type of progressive neurodegenerative disorder that results in cognitive impairment over time. Approximately 152million cases of AD are predicted to be reported by 2050. Amyloid plaques and tau proteins are two major hallmarks of AD which can be seen under electron microscope. Mitochondria plays a vital role in the pathogenesis of AD and mitochondria disruption leads to mitochondrial DNA (mtDNA) dysfunction, alteration of mitochondria dependent Ca2+ homeostasis, copper dysfunction, immune cell dysfunction, etc. In this review, we try to cover all the mechanisms related with mitochondrial dysfunction and mitochondrial pathogenesis that may help us to better understand AD as well as open a new era for therapeutic target of AD and treat this progressive disease.

Seed-induced Aβ deposition alters neuronal function and impairs olfaction in a mouse model of Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β (Aβ) which ultimately forms plaques. These Aβ deposits can be induced in APP transgenic mouse models by prion-like seeding. It has been widely accepted that anosmia and hyposmia occur during the early stages of AD, even before cognitive deficits are present. In order to determine the impact of seed-induced Aβ deposits on olfaction, we performed intracerebral injections of seed-competent brain homogenate into the olfactory bulb of young pre-depositing APP transgenic mice. Remarkably, we observed a dramatic olfactory impairment in those mice. Furthermore, the number of newborn neurons as well as the activity of cells in the mitral cell layer was decreased. Notably, exposure to an enriched environment reduced Aβ seeding, vivified neurogenesis and most importantly reversed olfactory deficits. Based on our findings, we conclude that altered neuronal function as a result of induced Aβ pathology might contribute to olfactory dysfunction in AD.

Trace Amine Associate Receptor 1 (TAAR1) as a New Target for the Treatment of Cognitive Dysfunction in Alzheimer's Disease.

Worldwide, approximately 27 million people are affected by Alzheimer’s disease (AD). AD pathophysiology is believed to be caused by the deposition of the β-amyloid peptide (Aβ). Aβ can reduce long-term potentiation (LTP), a form of synaptic plasticity that is closely associated with learning and memory and involves postsynaptic glutamate receptor phosphorylation and trafficking. Moreover, Aβ seems to be able to reduce glutamatergic transmission by increasing the endocytosis of NMDA receptors. Trace amines (TAs) are biogenic amines that are structurally similar to monoamine neurotransmitters. TAs bind to G protein-coupled receptors, called TAARs (trace amine-associated receptors); the best-studied member of this family, TAAR1, is distributed in the cortical and limbic structures of the CNS. It has been shown that the activation of TAAR1 can rescue glutamatergic hypofunction and that TAAR1 can modulate glutamate NMDA receptor-related functions in the frontal cortex. Several lines of evidence also suggest the pro-cognitive action of TAAR1 agonists in various behavioural experimental protocols. Thus, we studied, in vitro, the role of the TAAR1 agonist RO5256390 on basal cortical glutamatergic transmission and tested its effect on Aβ-induced dysfunction. Furthermore, we investigated, in vivo, the role of TAAR1 in cognitive dysfunction induced by Aβ infusion in Aβ-treated mice. In vitro data showed that Aβ 1–42 significantly decreased NMDA cell surface expression while the TAAR1 agonist RO5256390 promoted their membrane insertion in cortical cells. In vivo, RO5256390 showed a mild pro-cognitive effect, as demonstrated by the better performance in the Y maze test in mice treated with Aβ. Further studies are needed to better understand the interplay between TAAR1/Aβ and glutamatergic signalling, in order to evaluate the eventual beneficial effect in different experimental paradigms and animal models. Taken together, our data indicate that TAAR1 agonism may provide a novel therapeutic approach in the treatments of disorders involving Aβ-induced cognitive impairments, such as AD.

Activation of Wnt/β-catenin pathway mitigates blood-brain barrier dysfunction in Alzheimer's disease.

Alzheimer's disease is a neurodegenerative disorder that causes age-dependent neurological and cognitive declines. The treatments for Alzheimer's disease pose a significant challenge, because the mechanisms of disease are not being fully understood. Malfunction of the blood-brain barrier is increasingly recognized as a major contributor to the pathophysiology of Alzheimer's disease, especially at the early stages of the disease. However, the underlying mechanisms remain poorly characterized, while few molecules can directly target and improve blood-brain barrier function in the context of Alzheimer's disease. Here, we showed dysfunctional blood-brain barrier in patients with Alzheimer's disease reflected by perivascular accumulation of blood-derived fibrinogen in the hippocampus and cortex, accompanied by decreased tight junction proteins Claudin-5 and glucose transporter Glut-1 in the brain endothelial cells. In the APPswe/PS1dE9 (APP/PS1) mouse model of Alzheimer's disease, blood-brain barrier dysfunction started at 4 months of age and became severe at 9 months of age. In the cerebral microvessels of APP/PS1 mice and amyloid-β-treated brain endothelial cells, we found suppressed Wnt/β-catenin signalling triggered by an increase of GSK3β activation, but not an inhibition of the AKT pathway or switching to the Wnt/planar cell polarity pathway. Furthermore, using our newly developed optogenetic tool for controlled regulation of LRP6 (upstream regulator of the Wnt signalling) to activate Wnt/β-catenin pathway, blood-brain barrier malfunction was restored by preventing amyloid-β-induced brain endothelial cells impairments and promoting the barrier repair. In conclusion, targeting LRP6 in the Wnt/β-catenin pathway in the brain endothelium can alleviate blood-brain barrier malfunction induced by amyloid-β, which may be a potential treatment strategy for Alzheimer's disease.

Cysteine string protein alpha accumulates with early pre-synaptic dysfunction in Alzheimer's disease.

In Alzheimer’s disease, synapse loss causes memory and cognitive impairment. However, the mechanisms underlying synaptic degeneration in Alzheimer’s disease are not well understood. In the hippocampus, alterations in the level of cysteine string protein alpha, a molecular co-chaperone at the pre-synaptic terminal, occur prior to reductions in synaptophysin, suggesting that it is a very sensitive marker of synapse degeneration in Alzheimer’s. Here, we identify putative extracellular accumulations of cysteine string alpha protein, which are proximal to beta-amyloid deposits in post-mortem human Alzheimer’s brain and in the brain of a transgenic mouse model of Alzheimer’s disease. Cysteine string protein alpha, at least some of which is phosphorylated at serine 10, accumulates near the core of beta-amyloid deposits and does not co-localize with hyperphosphorylated tau, dystrophic neurites or glial cells. Using super-resolution microscopy and array tomography, cysteine string protein alpha was found to accumulate to a greater extent than other pre-synaptic proteins and at a comparatively great distance from the plaque core. This indicates that cysteine string protein alpha is most sensitive to being released from pre-synapses at low concentrations of beta-amyloid oligomers. Cysteine string protein alpha accumulations were also evident in other neurodegenerative diseases, including some fronto-temporal lobar dementias and Lewy body diseases, but only in the presence of amyloid plaques. Our findings are consistent with suggestions that pre-synapses are affected early in Alzheimer’s disease, and they demonstrate that cysteine string protein alpha is a more sensitive marker for early pre-synaptic dysfunction than traditional synaptic markers. We suggest that cysteine string protein alpha should be used as a pathological marker for early synaptic disruption caused by beta-amyloid.

Loss of LAMP5 interneurons drives neuronal network dysfunction in Alzheimer’s disease

In Alzheimer’s disease (AD), where amyloid-β (Aβ) and tau deposits in the brain, hyperexcitation of neuronal networks is an underlying disease mechanism, but its cause remains unclear. Here, we used the Collaborative Cross (CC) forward genetics mouse platform to identify modifier genes of neuronal hyperexcitation. We found LAMP5 as a novel regulator of hyperexcitation in mice, critical for the survival of distinct interneuron populations. Interestingly, synaptic LAMP5 was lost in AD brains and LAMP5 interneurons degenerated in different AD mouse models. Genetic reduction of LAMP5 augmented functional deficits and neuronal network hypersynchronicity in both Aβ- and tau-driven AD mouse models. To this end, our work defines the first specific function of LAMP5 interneurons in neuronal network hyperexcitation in AD and dementia with tau pathology.

Blood extracellular vesicles carrying synaptic function- and brain-related proteins as potential biomarkers for Alzheimer's disease.

Objective and accessible markers for Alzheimer's disease (AD) and other dementias are critically needed. We identified NMDAR2A, a protein related to synaptic function, as a novel marker of central nervous system (CNS)-derived plasma extracellular vesicles (EVs) and developed a flow cytometry-based technology for detecting such plasma EVs readily. The assay was initially tested in our local cross-sectional study to distinguish AD patients from healthy controls (HCs) or from Parkinson's disease (PD) patients, followed by a validation study using an independent cohort collected from multiple medical centers (the Alzheimer's Disease Neuroimaging Initiative). Cerebrospinal fluid AD molecular signature was used to confirm diagnoses of all AD participants. Likely CNS-derived EVs in plasma were significantly reduced in AD compared to HCs in both cohorts. Integrative models including CNS-derived EV markers and AD markers present on EVs reached area under the curve of 0.915 in discovery cohort and 0.810 in validation cohort. This study demonstrated that robust and rapid analysis of individual neuron-derived synaptic function-related EVs in peripheral blood may serve as a helpful marker of synaptic dysfunction in AD and dementia.

Impaired time-distance reconfiguration patterns in Alzheimer's disease: a dynamic functional connectivity study with 809 individuals from 7 sites

BackgroundThe dynamic functional connectivity (dFC) has been used successfully to investigate the dysfunction of Alzheimer's disease (AD) patients. The reconfiguration intensity of nodal dFC, which means the degree of alteration between FCs at different time scales, could provide additional information for understanding the reconfiguration of brain connectivity.ResultsIn this paper, we introduced a feature named time distance nodal connectivity diversity (tdNCD), and then evaluated the network reconfiguration intensity in every specific brain region in AD using a large multicenter dataset (N = 809 from 7 independent sites). Our results showed that the dysfunction involved in three subnetworks in AD, including the default mode network (DMN), the subcortical network (SCN), and the cerebellum network (CBN). The nodal tdNCD inside the DMN increased in AD compared to normal controls, and the nodal dynamic FC of the SCN and the CBN decreased in AD. Additionally, the classification analysis showed that the classification performance was better when combined tdNCD and FC to classify AD from normal control (ACC = 81%, SEN = 83.4%, SPE = 80.6%, and F1-score = 79.4%) than that only using FC (ACC = 78.2%, SEN = 76.2%, SPE = 76.5%, and F1-score = 77.5%) with a leave-one-site-out cross-validation. Besides, the performance of the three classes classification was improved from 50% (only using FC) to 53.3% (combined FC and tdNCD) (macro F1-score accuracy from 46.8 to 48.9%). More importantly, the classification model showed significant clinically predictive correlations (two classes classification: R = −0.38, P < 0.001; three classes classification: R = −0.404, P < 0.001). More importantly, several commonly used machine learning models confirmed that the tdNCD would provide additional information for classifying AD from normal controls.ConclusionsThe present study demonstrated dynamic reconfiguration of nodal FC abnormities in AD. The tdNCD highlights the potential for further understanding core mechanisms of brain dysfunction in AD. Evaluating the tdNCD FC provides a promising way to understand AD processes better and investigate novel diagnostic brain imaging biomarkers for AD.

The role of mitochondrial dysfunction in Alzheimer's disease: A potential pathway to treatment.

Alzheimer's disease (AD) is the most prevalent form of dementia worldwide and is characterized by progressive memory loss and cognitive impairment. Our understanding of AD pathogenesis is limited and no effective disease-modifying treatment is available. Mitochondria are cytoplasmic organelles critical to the homeostatic regulation of glucose and energy in the cell. Mitochondrial abnormalities are found early in the course of AD and dysfunctional mitochondria are involved in AD progression. The resulting respiratory chain impairment, neuronal apoptosis, and generation of reactive oxygen species are highly damaging to neurons. Restoration of mitochondrial function may provide a novel therapeutic strategy for AD. This review discusses the specifics of mitochondrial fragmentation, imbalances in fission and fusion, and DNA damage seen in AD and the contribution of compromised mitochondrial activity to AD etiopathogenesis. It explores how an understanding of the processes underlying mitochondrial failure may lead to urgently needed treatment innovations. It considers individual mitochondrial proteins that have emerged as promising drug targets and evaluates neuroprotective agents that could improve the functional state of mitochondria in the setting of AD. There is great promise in exploring original approaches to preserving mitochondrial viability as a means to achieve breakthroughs in treating AD.

A Silent Allosteric Modulator

Deterioration in cognitive dysfunction in Alzheimer’s disease (AD) patients is associated with microglia-mediated synaptic destruction. Using AD mouse models Spurrier and colleagues discerned the function of the metabotropic glutamate receptor 5 (mGluR5) on synaptic loss and demonstrated that a silent allosteric modulator (SAM) of mGLuR5 when given through the oral route successfully restored synaptic density and reduced phosphorylated TAU accumulation. The treatment in AD mice with SAM reversed the induced changes as a result of altered gene expression and blocked the synaptic confinement of the C1q complement protein. The findings of this study suggest that targeting mGluR5 with SAMs could be a powerful strategy for restricting AD-related synaptic loss. Sci. Transl. Med.14, eabi8593 (2022).

Signatures of somatosensory cortical dysfunction in Alzheimer's disease and HIV-associated neurocognitive disorder.

Alzheimer’s disease is the most common type of dementia in the general population, while HIV-associated neurocognitive disorder is the most common neurological comorbidity in those infected with HIV and affects between 40 and 70% of this population. Both conditions are associated with cognitive impairment and have been associated with aberrant functioning in sensory cortices, but far less is known about their disparate effects on neural activity. Identifying such disparate effects is important because it may provide critical data on the similarities and differences in the neuropathology underlying cognitive decline in each condition. In the current study, we utilized magnetoencephalography, extensive neuropsychological testing and a paired-pulse somatosensory gating paradigm to probe differences in somatosensory processing in participants from two ongoing magnetoencephalography studies. The resulting participant groups included 27 cognitively normal controls, 26 participants with HIV-associated neurocognitive disorder and 21 amyloid biomarker-confirmed patients with Alzheimer’s disease. The data were imaged using a beamformer and voxel time series were extracted to identify the oscillatory dynamics serving somatosensory processing, as well as the amplitude of spontaneous cortical activity preceding stimulation onset. Our findings indicated that people with Alzheimer’s disease and HIV-associated neurocognitive disorder exhibit normal somatosensory gating but have distinct aberrations in other elements of somatosensory cortical function. Essentially, those with Alzheimer’s disease exhibited accentuated neural responses to somatosensory stimulation, along with spontaneous gamma activity preceding stimulus onset. In contrast, those with HIV-associated neurocognitive disorder exhibited normal responses to somatosensory stimulation but had sharply elevated spontaneous gamma activity prior to stimulus onset. These distinct aberrations may reflect the impact of different neuropathological mechanisms underlying each condition. Further, given the differential pattern of deficits in somatosensory cortical function, these measures may function as unique biomarkers in each condition and be useful in identifying persons with HIV who may go on to develop Alzheimer’s disease.

The Role of Mesenchymal Stem Cells in Regulating Astrocytes-Related Synapse Dysfunction in Early Alzheimer's Disease.

Alzheimer’s disease (AD), a neurodegenerative disease, is characterized by the presence of extracellular amyloid-β (Aβ) aggregates and intracellular neurofibrillary tangles formed by hyperphosphorylated tau as pathological features and the cognitive decline as main clinical features. An important cellular correlation of cognitive decline in AD is synapse loss. Soluble Aβ oligomer has been proposed to be a crucial early event leading to synapse dysfunction in AD. Astrocytes are crucial for synaptic formation and function, and defects in astrocytic activation and function have been suggested in the pathogenesis of AD. Astrocytes may contribute to synapse dysfunction at an early stage of AD by participating in Aβ metabolism, brain inflammatory response, and synaptic regulation. While mesenchymal stem cells can inhibit astrogliosis, and promote non-reactive astrocytes. They can also induce direct regeneration of neurons and synapses. This review describes the role of mesenchymal stem cells and underlying mechanisms in regulating astrocytes-related Aβ metabolism, neuroinflammation, and synapse dysfunction in early AD, exploring the open questions in this field.

Far infrared light irradiation enhances Aβ clearance via increased exocytotic microglial ATP and ameliorates cognitive deficit in Alzheimer’s disease-like mice

BackgroundExposure to sunlight may decrease the risk of developing Alzheimer’s disease (AD), and visible and near infrared light have been proposed as a possible therapeutic strategy for AD. Here, we investigated the effects of the visible, near infrared and far infrared (FIR) light on the cognitive ability of AD mice, and found that FIR light also showed potential in the improvement of cognitive dysfunction in AD. However, the related mechanism remains to be elucidated.MethodsMorris water maze was used to evaluate the cognitive ability of APPswe/PSEN1dE9 double-transgenic AD mice after light treatment. Western blot was carried out to detect the expression of protein involved in synaptic function and amyloid-β (Aβ) production. The protein amount of interleukin (IL)-1β, IL-6, Aβ1-40 and Aβ1-42 were determined using enzyme-linked immunosorbent assay. The mRNA level of receptors was performed using real-time quantitative polymerase chain reaction. Immunostaining was performed to characterize the Aβ burden and microglial Aβ phagocytosis in the brain of AD mice. The Aβ phagocytosis of primary cultured microglia and BV2 were assessed by flow cytometry. The energy metabolism changes were evaluated using related assay kits, including adenosine triphosphate (ATP), lactate content, mitochondrial respiratory chain complex enzymatic activity and oxidized/reduced nicotinamide adenine dinucleotide assay kits.ResultsOur results showed that FIR light reduced Aβ burden, a hallmark of AD neuropathology, alleviated neuroinflammation, restored the expression of the presynaptic protein synaptophysin, and ameliorated learning and memory impairment in the AD mice. FIR light enhanced mitochondrial oxidative phosphorylation pathway to increase ATP production. This increased intracellular ATP promoted the extracellular ATP release from microglia stimulated by Aβ, leading to the enhanced Aβ phagocytosis through phosphoinositide 3-kinase/mammalian target of rapamycin pathways for Aβ clearance.ConclusionsOur findings have uncovered a previously unappreciated function of FIR light in inducing microglial phagocytosis to clean Aβ, which may be the mechanisms for FIR light to improve cognitive dysfunction in AD mice. These results suggest that FIR light treatment is a potential therapeutic strategy for AD.

Aesthetic Preference for Negatively-Valenced Artworks Remains Stable in Pathological Aging: A Comparison Between Cognitively Impaired Patients With Alzheimer's Disease and Healthy Controls.

BackgroundDespite severe cognitive dysfunction in Alzheimer's disease (AD), aesthetic preferences in AD patients seem to retain some stability over time, similarly to healthy controls. However, the underlying mechanisms of aesthetic preference stability in AD remain unclear. We therefore aimed to study the role of emotional valence of stimuli for stability of aesthetic preferences in patients with AD compared to cognitively unimpaired elderly adults.MethodsFifteen AD patients (Mini-Mental State Examination (MMSE) score 12–26) without visual impairment and/or psychiatric disorder, as well as 15 healthy controls without cognitive impairment (MMSE ≥ 27) matched in age, sex, art interest and highest level of education were included in this study. All participants were asked to rank-order eight artworks per stimulus category (positive, negative, neutral in emotional valence) according to their preference twice with a 2-week span in-between. Based on these two rankings a preference change score was calculated. In order to assess explicit recognition memory of the artworks in the second testing session, four artworks of each stimulus category used in the preference ranking task were presented together with a content-matched distractor artwork painted by the same artist. Participants had to indicate which of the stimuli they had seen 2 weeks previously.ResultsAD patients [MMSE (M) = 18.9 ± 3.6; Age (M) = 85.4 ± 6.9; 33.3% male] had no explicit recognition memory of the artworks (recognition at chance level), whereas healthy controls [MMSE (M) = 27.7 ± 1.4; Age (M) = 84.3 ± 6.7; 33.3% male] correctly recognized 85% of stimuli after 2 weeks. AD patients had equally stable preferences compared to the control group for negative artworks, but less stable preferences for positive and neutral images (Bonferroni-corrected significance levels; p < 0.017).ConclusionEven in cognitively impaired AD patients, aesthetic preference for negatively-valenced artworks remains relatively stable. Our study provides novel evidence that AD patients may have a somewhat preserved implicit valence system for negative compared to neutral or positive visual information, especially in the domain of aesthetics. However, more studies need to further uncover the details of the underlying neurocognitive mechanisms of preference stability in pathological aging.

0270 EEG Slow Wave Coherence is Related to PSG-Derived Measures of Sleep Fragmentation and Cognition in the WashU BASE Cohort

Abstract Introduction There exists a bidirectional relationship between sleep disruption and neuropathology in Alzheimer’s disease (AD). Electroencephalogram (EEG) during polysomnography (PSG) provides an opportunity to examine stereotyped, coordinated brain activity. Specifically, slow wave activity (SWA), a defining feature of non-REM sleep, is aberrant in AD, and disruption of SWA in healthy adults is related to increased amyloid-beta levels. Coherence of slow waves across different cortical regions may serve as a metric of brain network coordination, sensitive to earliest AD pathology. We explored slow wave coherence during sleep in relation to sleep macrostructure and cognitive performance in the Biomarkers of Alzheimer’s Disease in Sleep and EEG(BASE) cohort. Methods EEG was collected during an attended overnight PSG from the BASE cohort (n=79, average age = 70.8 ± 4.4 years), approximately 20% of whom had Clinical Dementia Rating (CDR) of 0.5-1. A custom slow wave peak detector was implemented in MATLAB to across 6 EEG leads (C3, C4, F3, F4, O1, and O2), and slow wavecoherence was calculated as the proportion of sleep with slow waves occurring within 100ms in all 6 leads. Results EEG slow wave coherence was reliably quantified during wake, non-REM stages N1, N2, N3, and REM. Slow wave coherence in N2/N3 was negatively correlated with measures of sleep fragmentation (wake after sleep onset Spearman r = -0.3, p 0.008; number of awakenings r = -0.39, p 0.0004), and positively correlated with sleep efficiency (r = 0.28, p = 0.013). Slow wave coherence in N2/N3 was correlated with overall cognition as measured by MoCA adjusted z-score (r = 0.2, p 0.087) and executive function as measured by Trailmaking B adjusted z-score (r = 0.25, p 0.038). Conclusion Slow wave coherence was strongly correlated with measures of sleep quality. Reduced slow wave coherence was associated with poorer cognitive executive function. EEG slow wave coherence is a novel, promising approach to measure coordinated brain network function that is sensitive to early cognitive dysfunction in AD. Support (If Any) NIH R01 AG059507, ARCS Foundation Scholar

MRTF-A-mediated protection against amyloid-β-induced neuronal injury correlates with restoring autophagy via miR-1273g-3p/mTOR axis in Alzheimer models.

Myocardia-Related Transcription Factors-A (MRTF-A), which is enriched in the hippocampus and cerebral cortex, has been shown to have a protective function against ischemia hypoxia-induced neuronal apoptosis. However, the function of MRTF-A on β-amyloid peptide (Aβ)-induced neurotoxicity and autophagy dysfunction in Alzheimer’s disease is still unclear. This study shows that the expression of MRTF-A in the hippocampus of Tg2576 transgenic mice is reduced, and the overexpression of MRTF-A mediated by lentiviral vectors carrying MRTF-A significantly reduces the accumulation of hippocampal β-amyloid peptide and reduces cognition defect. Overexpression of MRTF-A inhibits neuronal apoptosis, increases the protein levels of microtubule-associated protein 1 light chain 3-II (MAP1LC3/LC3-II) and Beclin1, reduces the accumulation of SQSTM1/p62 protein, and promotes autophagosomes-Lysosomal fusion in vivo and in vitro. Microarray analysis and bioinformatics analysis show that MRTF-A reverses Aβ-induced autophagy impairment by up-regulating miR-1273g-3p level leading to negative regulation of the mammalian target of rapamycin (mTOR), which is confirmed in Aβ1-42-treated SH-SY5Y cells. Further, overexpression of MRTF-A reduces Aβ1-42-induced neuronal apoptosis. And the effect was abolished by miR-1273g-3p inhibitor or MHY1485 (mTOR agonist), indicating that the protection of MRTF-A on neuronal damage is through targeting miR-1273g-3p/mTOR axis. Targeting this signaling may be a promising approach to protect against Aβ-induced neuronal injury.

Non-Apoptotic Caspase-3 Activation Mediates Early Synaptic Dysfunction of Indirect Pathway Neurons in the Parkinsonian Striatum.

Non-apoptotic caspase-3 activation is critically involved in dendritic spine loss and synaptic dysfunction in Alzheimer’s disease. It is, however, not known whether caspase-3 plays similar roles in other pathologies. Using a mouse model of clinically manifest Parkinson’s disease, we provide the first evidence that caspase-3 is transiently activated in the striatum shortly after the degeneration of nigrostriatal dopaminergic projections. This caspase-3 activation concurs with a rapid loss of dendritic spines and deficits in synaptic long-term depression (LTD) in striatal projection neurons forming the indirect pathway. Interestingly, systemic treatment with a caspase inhibitor prevents both the spine pruning and the deficit of indirect pathway LTD without interfering with the ongoing dopaminergic degeneration. Taken together, our data identify transient and non-apoptotic caspase activation as a critical event in the early plastic changes of indirect pathway neurons following dopamine denervation.