Early Phase Of Alzheimer's Disease Research Articles

Pharmacological enhancement of cholinergic neurotransmission alleviates neuroinflammation and improves functional outcomes in a triple transgenic mouse model of Alzheimer's disease.

Introduction: Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting the elderly population worldwide. Due to the multifactorial nature of the disease, involving impairment of cholinergic neurotransmission and immune system, previous attempts to find effective treatments have faced challenges. Methods: In such scenario, we attempted to investigate the effects of alpha-glyceryl-phosphoryl-choline (α-GPC), a cholinomimetic molecule, on neuroinflammation and memory outcome in the triple transgenic mouse model of AD (3xTg-AD). Mice were enrolled at 4 months of age, treated orally with α-GPC dissolved in drinking water at a concentration resulting in an average daily dose of 100mg/kg for 8 months and sacrificed at 12 months of age. Thereafter, inflammatory markers, as well as cognitive parameters, were measured. Results: Chronic α-GPC treatment reduced accumulation of amyloid deposits and led to a substantial re-balance of the inflammatory response of resident innate immune cells, astrocytes and microglia. Specifically, fluorescent immunohistochemistry and Western blot analysis showed that α-GPC contributed to reduction of cortical and hippocampal reactive astrocytes and pro-inflammatory microglia, concurrently increasing the expression of anti-inflammatory molecules. Whereas α-GPC beneficially affect the synaptic marker synaptophysin in the hippocampus. Furthermore, we observed that α-GPC was effective in restoring cognitive dysfunction, as measured by the Novel Object Recognition test, wherein 3xTg-AD mice treated with α-GPC significantly spent more time exploring the novel object compared to 3xTg-AD untreated mice. Discussion: In conclusion, chronic treatment with α-GPC exhibited a significant anti-inflammatory activity and sustained the key function of hippocampal synapses, crucial for the maintenance of a regular cognitive status. In light of our results, we suggest that α-GPC could be exploited as a promising therapeutic approach in early phases of AD.

Cerebrospinal Fluid Alzheimer's Disease Biomarker Patterns of Change Prior to the Onset of Mild Cognitive Impairment.

Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) are altered many years before the onset of clinical symptoms of mild cognitive impairment (MCI). Incorporating clinical symptom onset time into biomarker modeling may enhance our understanding of changes preceding MCI. Using a new analytical approach, we examined patterns of biomarker change prior to MCI symptom onset among individuals who progressed from normal cognition to MCI, stratified based on the age of symptom onset. We also analyzed biomarker patterns of change among participants who remained cognitively normal, and examined potential modifiers of biomarker trajectories, including demographics and apolipoprotein E (APOE) status. Analyses included 93 participants who progressed from normal cognition to MCI and 186 participants who remained cognitively normal, over an average follow-up period of 16.2 years. CSF biomarkers, including Aβ42, Aβ40, total tau (t-tau), and phosphorylated tau181 (p-tau181), were measured using the fully automated Lumipulse assays. Among participants who progressed to MCI, Aβ42/Aβ40 decreased, and t-tau and p-tau181 increased. For participants who did not progress to MCI, CSF biomarkers showed relatively stable patterns. In both progressors and non-progressors, APOE4 carriers showed lower Aβ 42/Aβ40 levels (compared to non-carriers) at each point of the mean curves. Among non-progressors, APOE4 carriers had higher levels of p-tau181, p-tau181/(Aβ 42/Aβ40), and t-tau/(Aβ 42/Aβ 40). Additionally, among those who did not progress, female sex was associated with higher levels of t-tau, p-tau181, t-tau/(Aβ 42/Aβ 40), and p-tau181/(Aβ 42/Aβ 40). These findings suggest that this analytic approach may provide additional insights into biomarker changes during early phases of AD.

NPTX2 in Cerebrospinal Fluid Predicts the Progression From Normal Cognition to Mild Cognitive Impairment.

This study examined whether cerebrospinal fluid (CSF) baseline levels of the synaptic protein NPTX2 predict time to onset of symptoms of mild cognitive impairment (MCI), both alone and when accounting for traditional CSF Alzheimer's disease (AD) biomarker levels. Longitudinal NPTX2 levels were also examined. CSF was collected longitudinally from 269 cognitively normal BIOCARD Study participants (mean baseline age = 57.7 years; mean follow-up = 16.3 years; n = 77 progressed to MCI/dementia). NPTX2 levels were measured from 3 correlated peptides using quantitative parallel reaction monitoring mass spectrometry. Levels of Aβ42 /Aβ40 , p-tau181 , and t-tau were measured from the same CSF specimens using Lumipulse automated electrochemiluminescence assays. In Cox regression models, lower baseline NPTX2 levels were associated with an earlier time to MCI symptom onset (hazard ratio [HR] = 0.76, SE = 0.09, p = 0.023). This association was significant for progression within 7 years (p = 0.036) and after 7 years from baseline (p = 0.001). Baseline NPTX2 levels improved prediction of time to MCI symptom onset after accounting for baseline AD biomarker levels (p < 0.01), and NPTX2 did not interact with the CSF AD biomarkers or APOE-ε4 genetic status. In linear mixed effects models, higher baseline p-tau181 and t-tau levels were associated with higher baseline levels of NPTX2 (both p < 0.001) and greater rates of NPTX2 declines over time. NPTX2 may be a valuable prognostic biomarker during preclinical AD that provides additive and independent prediction of MCI onset among individuals who are cognitively normal. We hypothesize that NPTX2-mediated circuit homeostasis confers resilience during the early phase of AD. ANN NEUROL 2023;94:620-631.

Baseline White Matter Neuroinflammation Predicts Cognitive Decline in Alzheimer Disease

AbstractBackgroundNeuroinflammation, an intrinsic immune response of the nervous system, is important in an early phase of Alzheimer Disease (AD) pathogenesis. However, it is largely unclear how neuroinflammation promotes the clinical progression of AD. Extracellular water edema (ECW) from Neuro‐inflammation imaging (NII), a diffusion‐based MRI approach for neuroinflammation, has been utilized to asses white matter (WM) neuroinflammation in AD. This study aims to investigate the relationship between WM neuroinflammation and longitudinal cognitive changes in AD.MethodThis study included 286 participants who were enrolled in ongoing research at the Knight ADRC at Washington University in Saint Louis. The CSF levels of Aβ42/Aβ40 and ptau181 measured with the automated Lumipulse platform were used to categorize the participants as being positive or negative amyloid (A) and tau (T), respectively (Table 1). As measures of cognitive performance, the Knight ADRC Preclinical Alzheimer Cognitive Composite (Knight ADRC‐PACC) and a Global composite score were employed for each individual. The rates of change of cognitive measures were calculated for each individual. The NII was acquired with a multi‐b value scheme (bmax =1400s/mm2 and 25 directions). The total WM neuroinflammation (NII‐ECW) was obtained using the TBSS (http://www.fmrib.ox.ac.uk/fsl) based WM skeleton. Randomise in FSL was utilized to examine voxel‐wise relationships between NII‐ECW and the rate of change of cognitive measures. Non‐parametric Kruskal‐Wallis and Chi‐square tests were employed for comparing continuous and categorical variables of the participants’ demographics, respectively. The group differences of NII‐ECW were tested using one‐way ANOVA. All statistical tests were conducted in R (R Core Team, 2020). Age, sex, and APOE ε4 carrier status were adjusted as covariates.Result Table 1 summarizes demographic data. When compared to the A‐T‐ group, the A+T+CDR0 and A+T+CDR0.5 groups had higher NII‐ECW (Figure 1). When the A+T+CDR1 group was compared to the other groups, there was no group difference in NII‐ECW. There were substantial negative associations between the NII‐ECW and the rates of change of cognitive measures in the widespread WM regions (Figure 2).ConclusionOur data suggest that neuroinflammation increases early in preclinical AD and decreases later in the disease. Furthermore, baseline neuroinflammation as measured by NII‐ECW predicts cognitive decline in AD.

Baseline White Matter Neuroinflammation Predicts Cognitive Decline in Alzheimer Disease

AbstractBackgroundNeuroinflammation, an intrinsic immune response of the nervous system, is important in an early phase of Alzheimer Disease (AD) pathogenesis. However, it is largely unclear how neuroinflammation promotes the clinical progression of AD. Extracellular water edema (ECW) from Neuro‐inflammation imaging (NII), a diffusion‐based MRI approach for neuroinflammation, has been utilized to asses white matter (WM) neuroinflammation in AD. This study aims to investigate the relationship between WM neuroinflammation and longitudinal cognitive changes in AD.MethodThis study included 286 participants who were enrolled in ongoing research at the Knight ADRC at Washington University in Saint Louis. The CSF levels of Aβ42/Aβ40 and ptau181 measured with the automated Lumipulse platform were used to categorize participants as being positive or negative amyloid (A) and tau (T), respectively (Table 1). As measures of cognitive performance, the Knight ADRC Preclinical Alzheimer Cognitive Composite (Knight ADRC‐PACC) and a Global composite score were employed for each individual. The rates of change of cognitive measures were calculated for each individual. The NII was acquired with a multi‐b value scheme (bmax =1400s/mm2 and 25 directions). The total WM neuroinflammation (NII‐ECW) was obtained using TBSS (http://www.fmrib.ox.ac.uk/fsl) based WM skeleton. Randomise in FSL was utilized to examine voxel‐wise relationships between NII‐ECW and the rate of change of cognitive measures. Non‐parametric Kruskal‐Wallis and Chi‐square tests were employed for comparing continuous and categorical variables of the participants’ demographics, respectively. The group differences of NII‐ECW were tested using one‐way ANOVA. All statistical tests were conducted in R (R Core Team, 2020). Age, sex, and APOE ε4 carrier status were adjusted as covariates.ResultTable 1 summarizes demographic data. When compared to the A‐T‐ group, the A+T+CDR0 and A+T+CDR0.5 groups had higher NII‐ECW (Figure 1). When the A+T+CDR1 group was compared to the other groups, there was no group difference in NII‐ECW. There were substantial negative associations between the NII‐ECW and the rates of change of cognitive measures in the widespread WM regions (Figure 2).ConclusionOur data suggest that neuroinflammation increases early in preclinical AD and decreases later in the disease. Furthermore, baseline neuroinflammation as measured by NII‐ECW predicts cognitive decline in AD.

Allopregnanolone potentiates bioenergetic capacity and mitochondrial biogenesis in astrocytes.

We reported previously that the neurosteroid allopregnanolone (Allo) promotes neural stem cell regeneration and differentiation, reverses neurogenic, metabolic and cognitive deficits and reduces Alzheimer's disease (AD) pathology in a mouse model of AD. To further investigate the cell-type specific mechanisms of Allo in regulating brain energy metabolism, we assessed the effect of Allo on mitochondrial bioenergetic profile and biogenesis in rat hippocampal astrocytes. E18 rat hippocampal astrocyte were cultured for 10 days in DMEM:F12(1:1) with 10% FBS and then starved in 10% Charcoal stripped-FBS / DMEM:F12 for 24 hours before treatment with 100nM Allo or 0.001% Vehicle overnight. Upon completion of treatment, cells were subject to morphological, biochemical, metabolic and transcriptomic characterization of their mitochondrial phenotypes. In primary hippocampal astrocytes, Allo significantly attenuates serum deprivation-induced bioenergetic deficits and oxidative stress by enhancing mitochondrial biogenesis and rebalancing mitochondrial dynamics. Allo treatment significantly enhances astrocytic mitochondrial biogenesis via Nrf1/Tfam signaling and reverses mitochondrial hyperfusion by elevating the ratio of mitochondrial fission protein Drp1 to the fusion protein Opa1. Functionally, Allo-induced improvement in bioenergetic function is coupled with reduced inflammasome activation in astrocytes. Outcomes of our findings further support the promising therapeutic effects of Allo against bioenergetic deficits that emerge in early phases of AD, with mitochondria being a major effector.

Modeling resting state MEG functional connectivity of the prodromal phase of AD using The Virtual Brain

AbstractBackgroundComputational multi‐scale brain modeling has been found to be a useful tool for identifying potential disease mechanisms in Alzheimer's disease (AD) [1]. Importantly, structural and functional disruption patterns of AD continuum arise from a chain of degeneration effects which take place even from the preclinical phase of the disease, which characterization has the potential to enable early intervention to counteract and delay cognitive decline.MethodMagnetoencephalography (MEG), T1‐ and dw‐ magnetic resonance imaging (MRI) have been gathered from 20 healthy controls (HC) and 20 mild cognitive impaired (MCI), to characterize their resting‐state functional connectivity (rsFC), and structural connectivity (SC) profiles. Regarding MEG signal, source reconstruction was performed with linearly constrained minimum variance beamformer and the obtained neural MEG sources were anatomically parcellated according to the Desikan‐Killiany atlas. Resting state activity of the participants has been characterized considering two FC indices (i.e., PLV and AEC) among relevant areas of the Default Mode Network (DMN). Personalized simulations of the 40 subjects have been carried out using The Virtual Brain software and the matching between real and simulated rsFC is finally evaluated. For the MCIs two different degradation patterns are introduced in the model, one based on the gray matter volumes, and one that takes in account white matter integrity.ResultThe inclusion of both types of degeneration patterns in key areas of the DMN results in an increase of the matching between real and simulated rsFC for MCI patients; the inclusion of both simultaneously brought the best results.ConclusionThis study shows how the inclusion of quantifiable signatures of structural degeneration regarding gray matter volumes and white matter integrity in multi‐scale brain models reflects to a better matching between real and simulated MEG‐rsFC, when modeling MCI patients. This complements the already existing studies in the field and provides new insights towards a precise characterization of patient's MEG resting state networks during the early phases of AD. 1 ‐ L. Stefanovski et al., “Linking Molecular Pathways and Large‐Scale Computational Modeling to Assess Candidate Disease Mechanisms and Pharmacodynamics in Alzheimer’s Disease,” Front Comput Neurosci, vol. 13, p. 54, 2019.

Overexpression of protein kinase Mζ in the hippocampal dentate gyrus rescues amyloid-β-induced synaptic dysfunction within entorhinal-hippocampal circuit

Entorhinal cortex (EC) is one of the first cerebral regions affected in the early phase of Alzheimer's disease (AD). Soluble forms of amyloid beta (Aβ) impair synaptic transmission in experimental AD models. Protein kinase Mζ (PKMζ) is an atypical persistently active protein kinase C, known to maintain long term synaptic plasticity and memory, but its role in AD has not yet been described. We examined effect of PKMζ overexpression on the late long-term potentiation (L-LTP) in the dentate gyrus (DG) following EC amyloidopathy. Oligomeric Aβ 1-42 (oAβ) or vehicle was bilaterally microinjected into the EC of the male Wistar rats. After 1 week, 2 µL of lentiviral vector (~108 TU/mL) encoding PKMζ genome was injected into the DG. One week later, synaptic responses and the LTP persistence were assessed in DG of freely moving animals during 90 minutes to 7 days period. Novel object recognition, passive avoidance and spatial memories were also tested. In rats with EC amyloidopathy, LTP was induced with less amplitude compared to the control group, and extinguished after 24 h. PKMζ overexpression in DG augmented synaptic responses (PS-LTP amplitudes) and maintained LTP over 1 week. PKMζ ameliorated recognition and memory deficits in rats with EC amyloidopathy. Microinjection of PKMζ inhibitor, zeta inhibitory peptide, into the DG abolished the boosting effect of PKMζ on synaptic activity and memory performance. PKMζ-dependent pathway could be a potential therapeutic target to combat synaptic failure and memory deficit in the early phase of AD.

Molecular mechanisms of neurodegeneration in the entorhinal cortex that underlie its selective vulnerability during the pathogenesis of Alzheimer's disease.

ABSTRACTThe entorhinal cortex (EC) is a vital component of the medial temporal lobe, and its contributions to cognitive processes and memory formation are supported through its extensive interconnections with the hippocampal formation. During the pathogenesis of Alzheimer's disease (AD), many of the earliest degenerative changes are seen within the EC. Neurodegeneration in the EC and hippocampus during AD has been clearly linked to impairments in memory and cognitive function, and a growing body of evidence indicates that molecular and functional neurodegeneration within the EC may play a primary role in cognitive decline in the early phases of AD. Defining the mechanisms underlying molecular neurodegeneration in the EC is crucial to determining its contributions to the pathogenesis of AD. Surprisingly few studies have focused on understanding the mechanisms of molecular neurodegeneration and selective vulnerability within the EC. However, there have been advancements indicating that early dysregulation of cellular and molecular signaling pathways in the EC involve neurodegenerative cascades including oxidative stress, neuroinflammation, glia activation, stress kinases activation, and neuronal loss. Dysfunction within the EC can impact the function of the hippocampus, which relies on entorhinal inputs, and further degeneration within the hippocampus can compound this effect, leading to severe cognitive disruption. This review assesses the molecular and cellular mechanisms underlying early degeneration in the EC during AD. These mechanisms may underlie the selective vulnerability of neuronal subpopulations in this brain region to the disease development and contribute both directly and indirectly to cognitive loss.This paper has an associated Future Leader to Watch interview with the first author of the article.

NGF and the Amyloid Precursor Protein in Alzheimer's Disease: From Molecular Players to Neuronal Circuits.

Alzheimer's disease (AD), one of the most common causes of dementia in elderly people, is characterized by progressive impairment in cognitive function, early degeneration of basal forebrain cholinergic neurons (BFCNs), abnormal metabolism of the amyloid precursor protein (APP), amyloid beta-peptide (Aβ) depositions, and neurofibrillary tangles. According to the cholinergic hypothesis, dysfunction of acetylcholine-containing neurons in the basal forebrain contributes markedly to the cognitive decline observed in AD. In addition, the neurotrophic factor hypothesis posits that the loss nerve growth factor (NGF) signalling in AD may account for the vulnerability to atrophy of BFCNs and consequent impairment of cholinergic functions. Though acetylcholinesterase inhibitors provide only partial and symptomatic relief to AD patients, emerging data from in vivo magnetic resonance imaging (MRI) and positron emission tomography (PET) studies in mild cognitive impairment (MCI) and AD patients highlight the early involvement of BFCNs in MCI and the early phase of AD. These data support the cholinergic and neurotrophic hypotheses of AD and suggest new targets for AD therapy.Different mechanisms account for selective vulnerability of BFCNs to AD pathology, with regard to altered metabolism of APP and tau. In this review, we provide a general overview of the current knowledge of NGF and APP interplay, focusing on the role of APP in regulating NGF receptors trafficking/signalling and on the involvement of NGF in modulating phosphorylation of APP, which in turn controls APP intracellular trafficking and processing. Moreover, we highlight the consequences of APP interaction with p75NTR and TrkAreceptor, which share the same binding site within the APP juxta-membrane domain. We underline the importance of insulin dysmetabolism in AD pathology, in the light of our recent data showing that overlapping intracellular signalling pathways stimulated by NGF or insulin can be compensatory. In particular, NGF-based signalling is able toameliorates deficiencies in insulin signalling in the medial septum of 3×Tg-AD mice. Finally, we present an overview of NGF-regulated microRNAs (miRNAs). These small non-coding RNAs are involved in post-transcriptional regulation of gene expression , and we focus on a subset that are specifically deregulated in AD and thus potentially contribute to its pathology.

Memory palaces to improve quality of life in Alzheimer's disease

AbstractBackgroundDementia is the problem of the future in health care. Dementia is hard for the person living with it, but even more burdensome for his/her environment. The conversational dialogue seems to decline. Dementia is more than memory‐loss, there is also communication‐loss. The primary objective is to examine whether the addition of (augmented) reality to communication strategies can reconnect subjects in the early phase of Alzheimer's Disease (AD) with their caregivers and family members. The secondary objective includes a follow‐up on quality of life (QOL‐AD), feelings of depression (GDS 15) and connectedness (QCPR) of subjects in the early phase of AD and their significant others.MethodWe have developed a mobile health‐application (MemoryHome) which allows caregivers to construct virtual scale models of the residential settings / at home situation. These models function as memory palaces in which photos of significant others are connected to the architectural, spatial environment. It is a visual‐audio‐guide through a well‐known environment and subjects in the early phase of AD can make this walk together with a caregiver or a family member.ResultOur intervention is non‐pharmacological, rather inexpensive, patient‐friendly, unconventional and easy to combine with regular treatment of Alzheimer’s disease. Data were collected in two different environments: in homecare and residential settings. Results showed a modest but positive relation with quality of life, connectedness between caregivers and their family members and the absence of feelings of geriatric depression.ConclusionThe mobile application MemoryHome is a convenient instrument to reinforce the dialogue that seemed to diminish between patients and their environment.The application allows participants to independently improve the recall and recognition of familiar faces.

Protective Role of Cerebrospinal Fluid Inflammatory Cytokines in Patients with Amnestic Mild Cognitive Impairment and Early Alzheimer's Disease Carrying Apolipoprotein E4 Genotype.

Neuroinflammatory cytokines can play a pivotal role in Alzheimer's disease (AD) contributing to the evolution of degenerative processes. We aimed at evaluating the levels of cerebrospinal fluid (CSF) inflammatory cytokines, chemokines, and growth factors in subjects with diagnosis of amnestic mild cognitive impairment and mild AD. We evaluated CSF contents of inflammatory cytokines in 66 patients divided according to the NIA-AA research framework and the APOE genotype. CSF of a group of cognitively unimpaired individuals (n = 23) was evaluated as control. All patients were evaluated for 24 months using Mini-Mental State Examination (MMSE). We found significant increased levels of IL-4, IL-6, IL-8, and G-CSF in the CSF of A+/T-APOE4 carriers, respect to A+/T-patients homozygous for APOE3, respect to A+/T+ patients, regardless the APOE status, and respect to controls. Over a period of 24 months, A+/T-APOE4 carriers, with increased levels of cytokines, showed a preserved cognitive evaluation when compared to the other subgroups of patients (delta MMSE at 24 months respect to baseline: 0.10±0.35; p < 0.05). Our data suggest that during early phases of AD, in APOE4 carriers, Aβ pathology likely induces a specific cytokines pattern synthesis associated to cognitive preservation. These data highlight the different role that neuroinflammation can play in AD pathology based on the presence of specific CSF biomarkers and on the APOE status.

Relationships Between Diffusion Tensor Imaging and Cerebrospinal Fluid Metrics in Early Stages of the Alzheimer's Disease Continuum.

Recently, the field of Alzheimer's disease (AD) research has adopted a new framework that places the progression of AD along a continuum consisting of a preclinical stage, followed by conversion to mild cognitive impairment, and ultimately dementia. Important neuropathological changes occur in the preclinical phase, necessitating the identification of metrics that can detect such early changes. While cerebrospinal fluid (CSF) measures of amyloid and tau are generally accepted as biomarkers of AD pathology, neuroimaging measures used to index white matter alterations throughout the brain remain less widely endorsed as candidate biomarkers. To explore the relationship between white matter alterations and AD pathology, we review the literature on multimodal studies that assessed both CSF markers and white matter indices, derived from diffusion tensor imaging (DTI) methods, across cohorts primarily in the early phases of AD. Our review indicates that abnormal CSF measures of Aβ42 and tau are associated with widespread alterations in white matter microstructure throughout the brain. Furthermore, white matter variability is related to individual differences in behavior and can aid in tracking longitudinal changes in cognition. Our review advocates for the utilization of DTI metrics in investigations of early AD and suggests that the combined use of DTI and CSF markers may better explain individual differences in cognition and disease progression. However, further research is needed to resolve certain mixed findings.

P3‐061: ALLOPREGNANOLONE POTENTIATES BIOENERGETIC CAPACITY AND RESTRUCTURES MITOCHONDRIAL RETICULUM IN NEURONS AND ASTROCYTES

We reported previously that the neurosteroid allopregnanolone (Allo) promotes neural stem cell regeneration, reverses neurogenic, metabolic and cognitive deficits and reduces Alzheimer's disease (AD) pathology in a mouse model of AD. To compare and contrast the cell-type specific mechanisms of Allo in regulating brain energy metabolism, we assessed the effect of Allo on mitochondrial bioenergetic profile and their morphological changes in rat hippocampal neurons and astrocytes. E18 rat hippocampal neurons were cultured for 10 days in neurobasal medium (NBM) with 2% B27 and then starved in 0.2% B27 / NBM for 4 hours before treatment with either 100nM Allo or 0.001% Vehicle overnight. E18 rat hippocampal astrocyte were cultured for 10 days in DMEM:F12(1:1) with 10% FBS and then starved in 10% Charcoal stripped-FBS / DMEM:F12 for 24 hours before treatment with 100nM Allo or 0.001% Vehicle overnight. Upon completion of treatment, both cell types were subject to morphological, biochemical and metabolic characterization of their mitochondrial phenotypes. In primary hippocampal neurons, Allo treatment significantly reversed nutrient deprivation-induced deficits in mitochondrial maximal- and spare respiratory capacity and dendritic morphology. In parallel, in primary hippocampal astrocytes, Allo rescued serum depletion-induced decline in mitochondrial spare respiratory capacity. Allo treatment reduced the population of less efficient swollen globule mitochondria in both neurons and astrocytes. Specifically in astrocytes, Allo decreased the number of hyperfused tubule mitochondria and increased small globule mitochondria. The effect of Allo on re-structuring nutrient or serum depletion-induced mitochondrial reticulum in both neurons and astrocytes was further supported by the restoration of the balance between Drp1 and Opa1 expression, which are key regulators for mitochondrial fission and fusion, respectively. Outcomes of our findings further support the promising therapeutic effects of Allo against bioenergetic deficits and mitochondrial inefficiency that emerge in early phases of AD, with mitochondrial dynamics being a potentially key targeted mechanism.

Microenvironment Remodeling Micelles for Alzheimer's Disease Therapy by Early Modulation of Activated Microglia.

Current strategies for Alzheimer's disease (AD) treatments focus on pathologies in the late stage of the disease progression. Poor clinical outcomes are displayed due to the irreversible damages caused by early microglia abnormality which triggers disease development before identical symptoms emerge. Based on the crosstalk between microglia and brain microenvironment, a reactive oxygen species (ROS)‐responsive polymeric micelle system (Ab‐PEG‐LysB/curcumin (APLB/CUR)) is reported to normalize the oxidative and inflammatory microenvironment and reeducate microglia from an early phase of AD. Through an β‐amyloid (Aβ) transportation‐mimicked pathway, the micelles can accumulate into the diseased regions and exert synergistic effects of polymer‐based ROS scavenging and cargo‐based Aβ inhibition upon microenvironment stimuli. This multitarget strategy exhibits gradual correction of the brain microenvironment, efficient neuroprotection, and microglia modulation, leading to decreased Aβ plaque burdens and consequently enhanced cognitive functions in APPswe/PSEN1dE9 model mice. The results indicate that microglia can be exploited as an early target for AD treatment and their states can be controlled via microenvironment modulation.

Soluble Aβ Oligomers Impair Dipolar Heterodendritic Plasticity by Activation of mGluR in the Hippocampal CA1 Region

SummarySoluble Aβ oligomers (oAβs) contribute importantly to synaptotoxicity in Alzheimer disease (AD), but the mechanisms related to heterogeneity of synaptic functions at local circuits remain elusive. Nearly all studies of the effects of oAβs on hippocampal synaptic plasticity have only examined homosynaptic plasticity. Here we stimulated the Schaffer collaterals and then simultaneously recorded in stratum radiatum (apical dendrites) and stratum oriens (basal dendrites) of CA1 neurons. We found that the apical dendrites are significantly more vulnerable to oAβ-mediated synaptic dysfunction: the heterosynaptic basal dendritic long-term potentiation (LTP) remained unchanged, whereas the homosynaptic apical LTP was impaired. However, the heterosynaptic basal dendritic plasticity induced by either spaced 10-Hz bursts or low-frequency (1-Hz) stimulation was disrupted by oAβs in a mGluR5-dependent manner. These results suggest that different firing patterns in the same neurons may be selectively altered by soluble oAβs in an early phase of AD, before frank neurodegeneration.

The association between hippocampal subfield volumes and education in cognitively normal older adults and amnestic mild cognitive impairment patients.

ObjectivePrevious research has indicated that there are potential associations between education and total hippocampal volume in the trajectory of Alzheimer’s disease (AD). However, the correlation between education and hippocampal subfield volumes in the progression of AD has yet to be understood. This study examined the relationship between education, which is a standard proxy for cognitive reserve, and hippocampal subfield volumes in healthy and amnestic mild cognitive impairment (aMCI) groups.Subjects and methodsThirty-eight subjects with aMCI and 39 healthy control subjects underwent 3 T magnetic resonance imaging, and hippocampal subfield volumes were measured by automated segmentation. Multiple linear regression analysis was used to determine the association between education and hippocampal subfield volumes.ResultsEducation had a significant negative correlation with the left parasubiculum, presubiculum, and subiculum volumes in the aMCI group. In addition, multiple subfield volumes including left parasubiculum, left/right presubiculum, left cornus ammonis (CA)3, and left CA4 showed a significant correlation with the neuropsychological test scores in the control group and aMCI group.ConclusionThese findings contribute to a better understanding of the association between education, hippocampal subfield volumes, and amnestic cognitive functions in the early phase of AD.

Correlation between Alzheimer disease and cataract

Alzheimer disease (AD) is a progressive neurodegenerative disease and is a leading cause of dementia among elders. In the early phase of AD, even if neuropathological changes presented, but little to none clinical symptoms were found. Therefore, it is difficult to diagnose AD in the beginning of the disease. It is vital to find a noninvasive way for both diagnose and prognosis of AD. Studies have found that β-amyloid (Aβ) works as a connection between AD and cataract. This review will discuss AD and its associated markers which may be present in the lens and cataract related AD to provide more basis for early diagnosis of AD. (Chin J Ophthalmol, 2017, 53: 314-316).

Hypoxia/ischemia activate processing of Amyloid Precursor Protein: impact of vascular dysfunction in the pathogenesis of Alzheimer's disease.

Alzheimer's disease (AD) is associated with deficiencies in cerebrovascular functions, e.g. reduced cerebral blood flow and capillary amyloid angiopathy, both of which are evident during the early phase of AD, thus local hypoxia/ischemia could augment the pathogenesis of AD. There is abundant literature revealing that exposures to hypoxia/ischemia increase the amyloidogenic processing of amyloid-β precursor protein (APP) leading to the accumulation of amyloid-β peptides in brain. This hypoxia-induced response has been attributed to a significant increase in the activities of β- and γ-secretases, whereas α-secretase activity decreases in hypoxia. Recent studies have indicated that hypoxia-inducible factor-1α (HIF-1α) stimulates the transcription of the β-secretase 1 (BACE1) gene through the hypoxia-response element in the BACE1 promoter. Moreover, HIF-1α protein can directly interact with the γ-secretase complex and increase its activity in a non-transcriptional manner. Hypoxia/ischemia also trigger endoplasmic reticulum stress and impair autophagy in brain, which consequently can stimulate the expression of presenilin 1 (PS1) and activate γ-secretase. Subsequently, PS1 protein can stabilize HIF-1α protein and in addition, APP intracellular domain peptide is able to induce the expression of HIF-1α. The activation of β- and γ-secretases is an evolutionarily conserved hypoxia response, e.g. it is also present in zebrafish. Given that β- and γ-secretases have many substrates in addition to APP, one could postulate that AD pathology is a byproduct of the rescue process mediated by these two aspartyl proteinases under hypoxic/ischemic conditions. We will review the recent evidence indicating that vascular dysfunctions can provoke AD pathology by activating β- and γ-secretases.

Decrease of high voltage Ca2+ currents in the dentate gyrus granule cells by entorhinal amyloidopathy is reversed by calcium channel blockade

In the Alzheimer's disease (AD), entorhinal-hippocampal circuit is one of the earliest affected networks. There are some evidences indicating abnormal neuronal excitability and impaired synaptic plasticity in the dentate gyrus (DG) of AD animal model. However, the underlying mechanism leading to DG dysfunction particularly in the early phase of AD is not known. Since calcium dyshomeostasis has a critical role in the etiology of AD, it is possible that this phenomenon precedes electrophysiological alteration in the DG. Here, the effect of the amyloid pathogenesis in the entorhinal cortex (EC) on high activated Ca2+ currents in the DG granule cells was investigated. One week after bilaterally injection of amyloid beta (Aβ) 1–42 into the EC, Ca2+ currents in the DG granule cells were assessed by whole cell patch clamp. Voltage clamp recording showed the amplitude of high voltage calcium currents in the DG granule cells was decreased following EC amyloidopathy. However, the Ca2+ current decay was slower than control. Double-pulse recording revealed that Ca2+-dependent inactivation of calcium current (CDI) was more pronounced in the EC-Aβ group compared to the control group. However, chronic treatment by calcium channel blocker (CCBs), isradipine or nimodipine, reverse the Ca2+ currents toward the control level. On the other hand, there was no significant difference in the calbindin level in the DG of different groups. In conclusion, our results suggest that Aβ in the EC independent of calbindin level triggers a decreased Ca2+ currents along with increased CDI in the DG granule cells which may lead to further electrophysiological alterations in these cells, and treatment by CCBs could preserve normal calcium current and may ultimately normal function against the Aβ toxicity.