Frontotemporal Lobar Dementia Mutant Tau Impairs Axonal Transport through a Protein Phosphatase 1γ-Dependent Mechanism

Pathologic tau modifications are characteristic of Alzheimer''s disease and related dementias, but mechanisms of tau toxicity continue to be debated. Inherited mutations in tau cause early onset frontotemporal lobar dementias (FTLD-tau) and are commonly used to model mechanisms of tau toxicity in tauopathies. Previous work in the isolated squid axoplasm model demonstrated that several pathogenic forms of tau inhibit axonal transport through a mechanism involving activation of protein phosphatase 1 (PP1). Here, we determined that P301L and R5L FTLD mutant tau proteins elicit a toxic effect on axonal transport as monomeric proteins. We evaluated interactions of wild-type or mutant tau with specific PP1 isoforms (α, β, and γ) to examine how the interaction contributes to this toxic effect using primary rat hippocampal neurons from both sexes. Pull-down and bioluminescence resonance energy transfer experiments revealed selective interactions of wild-type tau with PP1α and PP1γ isoforms, but not PP1β, which were significantly increased by the P301L tau mutation. The results from proximity ligation assays confirmed the interaction in primary hippocampal neurons. Moreover, expression of FTLD-linked mutant tau in these neurons enhanced levels of active PP1, also increasing the pausing frequency of fluorescently labeled vesicles in both anterograde and retrograde directions. Knockdown of PP1γ, but not PP1α, rescued the cargo-pausing effects of P301L and R5L tau, a result replicated by deleting a phosphatase-activating domain in the amino terminus of P301L tau. These findings support a model of tau toxicity involving aberrant activation of a specific PP1γ-dependent pathway that disrupts axonal transport in neurons.SIGNIFICANCE STATEMENT Tau pathology is closely associated with neurodegeneration in Alzheimer''s disease and other tauopathies, but the toxic mechanisms remain a debated topic. We previously proposed that pathologic tau forms induce dysfunction and degeneration through aberrant activation of a PP1-dependent pathway that disrupts axonal transport. Here, we show that tau directly interacts with specific PP1 isoforms, increasing levels of active PP1. Pathogenic tau mutations enhance this interaction, further increasing active PP1 levels and impairing axonal transport in isolated squid axoplasm and primary hippocampal neurons. Mutant-tau-mediated impairment of axonal transport was mediated by PP1γ and a phosphatase-activating domain located at the amino terminus of tau. This work has important implications for understanding and potentially mitigating tau-mediated neurotoxicity in tauopathies.     

Network interdigitations of Tau and amyloid‐beta deposits define cognitive levels in aging

Amyloid‐beta (Aβ) plaques and tau neurofibrillary tangles are pathological hallmarks of Alzheimer''s disease (AD); their contribution to neurodegeneration and clinical manifestations are critical in understanding preclinical AD. At present, the mechanisms related to Aβ and tau pathogenesis leading to cognitive decline in older adults remain largely unknown. Here, we examined graph theory‐based positron emission tomography (PET) analytical approaches, within and between tau and Aβ PET modalities, and tested the effects on cognitive changes in cognitively normal older adults (CN). Particularly, we focused on the network interdigitations of Aβ and tau deposits, along with cognitive test scores in CN at both baseline and 2‐year follow‐up (FU). We found highly significant Aβ‐tau network integrations in AD vulnerable areas, as well as significant associations between those Aβ‐tau interdigitations and general cognitive impairment in CN at baseline and FU. Our findings suggest a distinctive contribution of interlinking network relationships between Aβ and tau deposits in heteromodal areas of the human brain. They support a network‐based interaction between Aβ and tau accumulations as a key factor for cognitive deterioration in CN prior to dementia.     

Association of the Tau haplotype with Parkinson's disease in the Greek population.

We compared the distribution of the Tau H1 haplotype and related subhaplotypes in a group of clinically diagnosed Parkinson's disease patients (n = 133) and in control individuals (n = 113) from northern Greece. We were able to detect a statistically significant overrepresentation of the H1H1 genotype in our patient group (OR for H1H1 vs. H1H2 and H2H2: 1.73; 95% CI: 1.03-2.90; P = 0.037). The H1 subhaplotype significantly associated with the disease in our population was different from the one previously reported for a Norwegian population, suggesting that the nature of the association of Tau with Parkinson's disease is influenced by ethnic variation.     

Sirt1 overexpression in neurons promotes neurite outgrowth and cell survival through inhibition of the mTOR signaling

The mammalian nicotinamide-adenine dinucleotide (NAD)-dependent deacetylase Sirt1 impacts different processes involved in the maintenance of brain integrity and in the pathogenic pathways associated with several neurodegenerative disorders, including Alzheimer's disease. Here we used human Sirt1 transgenic mice to demonstrate that neuron-specific Sirt1 overexpression promoted neurite outgrowth and improved cell viability under normal and nutrient-limiting conditions in primary culture systems and that Sirt1-overexpressing neurons exhibited higher tolerance to cell death or degeneration induced by amyloid-β1-42 oligomers. Coincidentally, we found that enhanced Sirt1 expression in neurons downregulated the mammalian target of rapamycin (mTOR) protein levels and its phosphorylation without changes in its mRNA levels, which was accompanied by concomitant inhibition of the mTOR downstream signaling activity as revealed by decreased p70S6 kinase (p70S6K) phosphorylation at Thr389. Consistently with this, using a Sirt1 siRNA transfection approach, we observed that reduction of endogenous mouse Sirt1 led to increased levels of mTOR and phosphorylation of itself and p70S6K as well as impaired cell survival and neurite outgrowth in wild-type mouse primary neurons, corroborating a suppressing effect of mTOR by Sirt1. Correspondingly, the mTOR inhibitor rapamycin markedly improved neuronal cell survival in response to nutrient deprivation and significantly enhanced neurite outgrowth in wild-type mouse neurons. The protective effect of rapamycin was extended to neurons even with Sirt1 siRNA knockdown that displayed developmental abnormalities compared with siRNA control-treated cells. Collectively, our findings suggest that Sirt1 may act to promote growth and survival of neurons in the central nervous system via its negative modulation of mTOR signaling.     

Factors Associated with Caregiver Burden in Patients with Alzheimer's Disease

Objective

Caregivers for patients with Alzheimer''s disease (AD) suffer from psychological and financial burdens. However, the results of the relationship between burden and cognitive function, performance of activities of daily living, and depressive symptoms have remained inconsistent. Therefore, the aim of this study was to examine which factors are more significant predictors of heightened burden, cognitive impairment or functional decline, besides neuropsychiatric symptoms.

Methods

A cross-sectional study was conducted in a sample comprised of 1,164 pairs of patients with AD and caregivers from the Clinical Research of Dementia of South Korea study cohorts. The cognitive function of each sub-domain, functional impairments, depressive symptoms, and caregiver burden were assessed using the dementia version of Seoul Neuropsychological Screening Battery (SNSB-D), Barthel Index for Daily Living Activities (ADL), Seoul-Instrumental Activities of Daily Living (S-IADL), the Clinical Dementia Rating Sum of Box (CDR-SB), the Global Deterioration Scale (GDS), the Korean version of the Neuropsychiatric Inventory (K-NPI), and the 15-item Geriatric Depression Scale.

Results

We found that higher severity (higher CDR-SB and GDS scores) and more functional impairment (lower ADL and higher S-IADL scores) were significantly associated with higher caregiver burden. In addition, depressive symptoms of patients (higher Geriatric Depression Scale scores) were associated with higher caregiver burden.

Conclusion

Therefore, interventions to help maintain activities of daily living in patients with AD may alleviate caregiver burden and improve caregiver well-being.     

AMPA-selective glutamate receptor subtype immunoreactivity in the aged human hippocampal formation

It has been hypothesized that, in Alzheimer's disease, glutamate-mediated excitotoxicity contributes to the degeneration of selected populations of neurons. In the present study, immunocytochemical techniques were used to determine the distribution and anatomical features of GluR1- and GluR2/3-immunolabeled cell bodies and processes within the hippocampal formation of normal (i.e., no pathology) elderly humans. The results of this study provide an essential baseline with which to compare the expression and distribution of glutamate receptor subunits within the brains of patients with Alzheimer's disease. With respect to GluR1 immunoreactivity, the molecular layer of the dentate gyrus displays the most intense immunolabeling of any hippocampal structure. Contributing to this intense labeling are apical dendrites that arise from neurons within the adjacent granule cell layer. Interestingly, GluR1-labeled neurons account for a relatively small percentage of the total number of neurons as revealed by Nissl staining in the granule cell layer. In contrast, GluR2/3-labeled neurons are densely distributed throughout the granule cell layer, yet they provide relatively few processes to the adjacent molecular layer compared to GluR1-positive processes. GluRl labeling is also prominent within the CA fields of Ammon's horn, with CA2 > CA3 > CA1 ≥ CA4. Most prominent within the CA fields are the labeled dendrites of pyramidal neurons. In many instances, apical dendrites can be traced into the adjacent stratum radiatum, where they impart a deep striated appearance to this region of the hippocampus. Robust GluR2/3 labeling is also observed within the pyramidal layer of Ammon's horn, with an order of staining intensity similar to that observed for GluRl. However, unlike GluRl labeling, which is localized predominantly along dendrites, GluR2/3 labeling is observed primarily in association with ceh bodies. Collectively, these data suggest that the molecular composition of the AMPA receptor complex may differ between the dendrite and soma of granule and pyramidal neurons within the hippocampal formation, so functionally we may predict that these two regions of the neuron would respond differently following glutamate receptor stimulation. © 1995 Wiley-Liss, Inc.     

Sleep Problems Associated with Behavioral and Psychological Symptoms as Well as Cognitive Functions in Alzheimer's Disease

Background and Purpose

It has been shown that sleep problems in Alzheimer''s disease (AD) are associated with cognitive impairment and behavioral problems. In fact, most of studies have founded that daytime sleepiness is significantly correlated with cognitive decline in AD. However, a few studies have also shown that nighttime sleep problems are associated with cognitive function and behavioral symptoms in AD. Accordingly, the aim of this study was to evaluate the effects of nighttime sleep on cognition and behavioral and psychological symptoms of dementia (BPSD) in AD.

Methods

The study population comprised 117 subjects: 63 AD patients and 54 age- and sex-matched non-demented elderly subjects. Detailed cognitive functions and behavioral symptoms were measured using the Seoul Neuropsychological Screening Battery (SNSB) and the Korean version of the Neuropsychiatric Inventory (NPI-K). Sleep characteristics were evaluated using the Korean version of the Pittsburgh Sleep Quality Index (PSQI-K). The correlations between PSQI-K and SNSB scores and between PSQI-K and NPI-K scores were analyzed.

Results

In AD patients, sleep latency was found to be negatively correlated with praxis (p=0.041), Rey-Osterrieth Complex Figure Test (RCFT) immediate recall (p=0.041), and RCFT recognition (p=0.008) after controlling for age and education, while sleep duration and sleep efficiency were positively correlated with praxis (p=0.034 and p=0.025, respectively). Although no significant correlation was found between PSQI-K and NPI-K scores, sleep disturbance and total PSQI-K scores were found to be significantly associated with apathy/indifference in AD.

Conclusions

Sleep problems such as prolonged sleep duration, sleep latency, and poor sleep efficiency in AD patients were correlated with cognitive dysfunction, and especially frontal executive and visuospatial functions, and BPSD. These findings suggest that treatment of nighttime sleep problems might improve cognition and behavioral symptoms in AD patients.     

Tau and β-Amyloid Burden Predict Actigraphy-Measured and Self-Reported Impairment and Misperception of Human Sleep

Alzheimer''s disease is associated with poor sleep, but the impact of tau and β-amyloid (Aβ) pathology on sleep remains largely unknown. Here, we test the hypothesis that tau and Aβ predict unique impairments in objective and self-perceived human sleep under real-life, free-living conditions. Eighty-nine male and female cognitively healthy older adults received ¹⁸F-FTP-tau and ¹¹C-PIB-Aβ PET imaging, 7 nights of sleep actigraphy and questionnaire measures, and neurocognitive assessment. Tau burden, but not Aβ, was associated with markedly worse objective sleep. In contrast, Aβ and tau were associated with worse self-reported sleep quality. Of clinical relevance, Aβ burden predicted a unique perceptual mismatch between objective and subject sleep evaluation, with individuals underestimating their sleep. The magnitude of this mismatch was further predicted by worse executive function. Thus, early-stage tau and Aβ deposition are linked with distinct phenotypes of real-world sleep impairment, one that includes a cognitive misperception of their own sleep health.SIGNIFICANCE STATEMENT Alzheimer''s disease is associated with sleep disruption, often before significant memory decline. Thus, real-life patterns of sleep behavior have the potential to serve as a window into early disease progression. In 89 cognitive healthy older adults, we found that tau burden was associated with worse wristwatch actigraphy-measured sleep quality, and that both tau and β-amyloid were independently predictive of self-reported sleep quality. Furthermore, individuals with greater β-amyloid deposition were more likely to underestimate their sleep quality, and sleep quality underestimation was associated with worse executive function. These data support the role of sleep impairment as a key marker of early Alzheimer''s disease, and offer the possibility that actigraphy may be an affordable and scalable tool in quantifying Alzheimer''s disease-related behavioral changes.     

Development and evaluation of [125I]IPPI for Tau imaging in postmortem human Alzheimer's disease brain

Objective: Alzheimer's disease (AD) is a neurodegenerative disease characterized by aggregation of Tau protein into paired helical filaments causing neurofibrillary tangles (NFT) in the brain. The aim of this study was to develop and evaluate the effectiveness of a novel radioiodinated tracer, 6‐[¹²⁵I]iodo‐3‐(1H‐pyrrolo[2,3‐c]pyridine‐1‐yl)isoquinoline ([¹²⁵I]IPPI), for binding to Tau protein (Ki = 0.75 nM) in postmortem human brain (AD and cognitively normal (CN). Methods: Radiosynthesis of [¹²⁵I]IPPI was carried out by radioiododestannylation and purified chromatographically. Computational modeling studies of IPPI and MK‐6240 binding on Tau fibril were evaluated. In vitro autoradiography studies were carried out with [³H]PIB for Aβ plaques and [¹²⁵I]IPPI for Tau in AD and CN brains and evaluate drug effects. Results: [¹²⁵I]IPPI was produced in >95% purity. Molecular modeling of IPPI revealed binding energies of IPPI (?7.8, ?8.1, ?8.2, ?7.5 Kcal/mol) at the four sites were comparable to MK‐6240 (?8.7, ?8.5, ?8.3, ?7.5 Kcal/mol). Ratio of average grey matter (GM) [¹²⁵I]IPPI in AD versus CN was found to be 7.31 (p = .07) and AD GM/ white matter (WM) = 4.35 (p = .09). Ratio of average GM/WM [¹²⁵I]IPPI in CN was 1.21. Binding of [¹²⁵I]IPPI correlated with the presence of Tau, confirmed by anti‐Tau Dako A0024. Specifically bound [¹²⁵I]IPPI to Tau in AD brains was displaced by MK‐6240 and IPPI (>90%). Monoamine oxidase inhibitors (MAO) inhibitors deprenyl and clorgyline effected [¹²⁵I]IPPI binding at >1 µM concentrations. Conclusion: [¹²⁵I]IPPI exhibited high binding in human AD frontal cortex and anterior cingulate and is a suitable radioiodinated ligand for Tau imaging.     

Sodium tungstate decreases the phosphorylation of tau through GSK3 inactivation

Tungstate treatment increases the phosphorylation of glycogen synthase kinase-3beta (GSK3beta) at serine 9, which triggers its inactivation both in cultured neural cells and in vivo. GSK3 phosphorylation is dependent on the activation of extracellular signal-regulated kinases 1/2 (ERK1/2) induced by tungstate. As a consequence of GSK3 inactivation, the phosphorylation of several GSK3-dependent sites of the microtubule-associated protein tau decreases. Tungstate reduces tau phosphorylation only in primed sequences, namely, those prephosphorylated by other kinases before GSK3beta modification, which are serines 198, 199, or 202 and threonine 231. The phosphorylation at these sites is involved in reduction of the interaction of tau with microtubules that occurs in Alzheimer's disease.     

Plasma Total Homocysteine Levels are not Associated with Medial Temporal Lobe Atrophy, but with White Matter Changes in Alzheimer's Disease

Background and purpose

Elevated plasma total homocysteine (tHcy) levels are reported to be associated with an increased risk of Alzheimer''s disease (AD). However, the mechanism by which homocysteine contributes to the pathogenesis of AD is as yet unknown. The aim of this study was to elucidate the relationship between white matter changes (WMC) and medial temporal lobe atrophy (MTA) on brain magnetic resonance imaging (MRI), and plasma levels of tHcy in AD patients.

Methods

Seventy-two patients with a clinical diagnosis of probable AD were recruited to the study. Plasma tHcy levels, vascular risk factors, and WMC and MTA on brain MRI were evaluated in all patients. The AD patients were classified into two groups: those with no or minimal WMC (69.2±8.8 years, mean±SD, n=36) and those with moderate-to-severe WMC (74.6±4.6 years, n=36) on brain MRI.

Results

In a univariate logistic regression analysis, the risk of moderate-to-severe WMC in AD was significantly associated with increasing age, female gender, lower education level, hypertension, high plasma tHcy levels, and lower Mini-Mental State Examination (MMSE) score. Multivariate logistic regression analysis revealed only high plasma tHcy as the independent and significant risk factor for moderate-to-severe WMC [odds ratio (OR; adjusted for age, gender, education level, MMSE score, and hypertension comparing the top tertile - tHcy levels ≥12.9 µmol/L - with the bottom tertile - tHcy levels ≤9.4 µmol/L)=7.35; 95% confidence interval, confidence interval=1.36-39.84; p=0.02], and age as a borderline significant risk factor (OR=1.08, 95% CI=0.99-1.19, p=0.09) in AD patients. Plasma tHcy levels were not correlated significantly with either right or left MTA.

Conclusions

Our results suggest that the vascular pathway mediates the association between elevated plasma tHcy levels and AD.     

G1/S Cell Cycle Checkpoint Defect in Lymphocytes from Patients with Alzheimer's Disease

Objective

We compared the cell responsiveness of activated lymphocytes to rapamycin, which blocks the G1/S transition, between patients with Alzheimer''s disease (AD) and normal controls to assess the early phase control defect in cell cycle.

Methods

Blood samples of 26 patients with AD and 28 normal controls were collected to separate peripheral lymphocytes. We measured the proportion of each cell cycle phase in activated lymphocytes using flow cytometry and evaluated the responsiveness of these lymphocytes to rapamycin.

Results

The patients with AD were older than the normal controls (AD 74.03±7.90 yr vs. control 68.28±6.21 yr, p=0.004). The proportion of G1 phase cells in the AD group was significantly lower than that in the control group (70.29±6.32% vs. 76.03±9.05%, p=0.01), and the proportion of S phase cells in the AD group was higher than that in control group (12.45±6.09% vs. 6.03±5.11%, p=0.001). Activated lymphocytes in patients with AD were not arrested in the G1 phase and they progressed to the late phase of the cell cycle despite rapamycin treatment, in contrast to those of normal subjects.

Conclusion

The patients with AD probably have a control defect of early phase cell cycle in peripheral lymphocytes that may be associated with the underlying pathology of neuronal death.     

Selective astrocytic endothelin-1 overexpression contributes to dementia associated with ischemic stroke by exaggerating astrocyte-derived amyloid secretion

Endothelin-1 (ET-1) is synthesized by endothelial cells and astrocytes in stroke and in brains of Alzheimer''s disease patients. Our transgenic mice with ET-1 overexpression in the endothelial cells (TET-1) showed more severe blood–brain barrier (BBB) breakdown, neuronal apoptosis, and glial reactivity after 2-hour transient middle cerebral artery occlusion (tMCAO) with 22-hour reperfusion and more severe cognitive deficits after 30 minutes tMCAO with 5 months reperfusion. However, the role of astrocytic ET-1 in contributing to poststroke cognitive deficits after tMCAO is largely unknown. Therefore, GET-1 mice were challenged with tMCAO to determine its effect on neurologic and cognitive deficit. The GET-1 mice transiently displayed a sensorimotor deficit after reperfusion that recovered shortly, then more severe deficit in spatial learning and memory was observed at 3 months after ischemia compared with that of the controls. Upregulation of TNF-α, cleaved caspase-3, and Thioflavin-S-positive aggregates was observed in the ipsilateral hemispheres of the GET-1 brains as early as 3 days after ischemia. In an in vitro study, ET-1 overexpressing astrocytic cells showed amyloid secretion after hypoxia/ischemia insult, which activated endothelin A (ETA) and endothelin B (ETB) receptors in a PI3K/AKT-dependent manner, suggesting role of astrocytic ET-1 in dementia associated with stroke by astrocyte-derived amyloid production.     

Distinct Factors Drive the Spatiotemporal Progression of Tau Pathology in Older Adults

Mechanisms underlying the initial accumulation of tau pathology across the human brain are largely unknown. We examined whether baseline factors including age, amyloid-β (Aβ), and neural activity predicted longitudinal tau accumulation in temporal lobe regions that reflect distinct stages of tau pathogenesis. Seventy cognitively normal human older adults (77 ± 6 years, 59% female) received two or more ¹⁸F-flortaucipir (FTP) and ¹¹C-Pittsburgh Compound B (PiB) PET scans (mean follow-up, 2.5 ± 1.1 years) to quantify tau and (Aβ). Linear mixed-effects models were used to calculate the slopes of FTP change in entorhinal cortex (EC), parahippocampal cortex (PHC), and inferior temporal gyrus (IT), and slopes of global PiB change. Thirty-seven participants underwent functional MRI to measure baseline activation. Older age predicted EC tau accumulation, and baseline EC tau levels predicted subsequent tau accumulation in EC and PHC. In IT, however, baseline EC tau interacted with Aβ to predict IT tau accumulation. Higher baseline local activation predicted tau accumulation within EC and PHC, and higher baseline hippocampal activation predicted EC tau accumulation. Our findings indicate that factors predicting tau accumulation vary as tau progresses through the temporal lobe. Older age is associated with initial tau accumulation in EC, while baseline EC tau and neural activity drive tau accumulation within medial temporal lobe. Aβ subsequently facilitates tau spread from medial to lateral temporal lobe. Our findings elucidate potential drivers of tau accumulation and spread in aging, which are critical for understanding Alzheimer''s disease pathogenesis.SIGNIFICANCE STATEMENT To further understand the mechanisms leading to tau pathogenesis and spread, we tested whether baseline factors such as age, amyloid-β pathology, and activation predicted longitudinal tau accumulation in cognitively normal older adults. We found that distinct mechanisms contribute to tau accumulation as tau progresses across the temporal lobe, with initial tau accumulation in entorhinal cortex driven by age and subsequent spread driven by neural activity and amyloid-β. We demonstrate that higher baseline activation predicts increased longitudinal tau accumulation, providing novel evidence that activation-dependent tau production may occur in the human brain. Our findings support major hypotheses generated from preclinical research, and have important translational implications, suggesting that the reduction of hyperactivation may help prevent the development of tau pathology.     

An 1H-MRS framework predicts the onset of Alzheimer's disease symptoms in PSEN1 mutation carriers

BackgroundAlzheimer's disease (AD) is the most common cause of dementia; the main risk factors are age and several recently identified genes. A major challenge for AD research is the early detection of subjects at risk. The aim of this study is to develop a predictive model using proton magnetic resonance spectroscopy (¹H-MRS), a noninvasive technique that evaluates brain chemistry in vivo, for monitoring the clinical outcome of carriers of a fully penetrant mutation that causes AD.MethodsWe studied 75 subjects from the largest multigenerational pedigree in the world (∼5000 people) that segregates a unique form of early-onset Alzheimer's disease (EOAD) caused by a fully penetrant mutation in the Presenilin-1 gene (PSEN1 p.Glu280Ala [E280 A]). Forty-four subjects were carriers of the mutation, and 31 were noncarriers. Seventeen carriers had either mild cognitive impairment (MCI) or early-stage AD (collectively MCI-AD). In right and left parietal white mater and parasagittal parietal gray matter (RPPGM and LPPGM) of the posterior cingulate gyrus and precuneus, we measured levels of the brain metabolites N-acetylaspartate (NAA), inositol (Ins), choline (Cho), and glutamate-glutamine complex (Glx) relative to creatine (Cr) levels (NAA/Cr, Ins/Cr, Cho/Cr, and Glx/Cr, respectively) with two-dimensional ¹H-MRS. Using advanced recursive partition analysis and random forest analysis, we built classificatory decision trees for both mutation carrier status and the presence of MCI-AD symptoms, fitting them to ¹H-MRS data while controlling for age, educational level, and sex.ResultsWe found that (1) the combination of LPPGM Cho/Cr <0.165 and RPPGM Glx/Cr >1.54 fully excluded carriers; (2) LPPGM Cho/Cr >0.165, RPPGM Glx/Cr <1.54, and left parietal white mater NAA/Cr >1.16 identified asymptomatic carriers with sensitivity of 97.7% and specificity of 77.4%; and (3) RPPGM NAA/Cr >1.05 defined asymptomatic subjects (independent of carrier status) with sensitivity of 100% and a specificity of 96.6%.ConclusionsBrain metabolites measured by ¹H-MRS in the posterior cingulate gyrus and precuneus are optimally sensitive and specific potential noninvasive biomarkers of subclinical emergence of AD caused by the PSEN1 p.Glu280Ala (E280 A) mutation.     

Prevention of tau increase in cerebrospinal fluid of APP transgenic mice suggests downstream effect of BACE1 inhibition

Introduction

The inhibition of the β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is a main therapeutic approach for the treatment of Alzheimer's disease (AD). We previously reported an age-related increase of tau protein in the cerebrospinal fluid (CSF) of amyloid β (Aβ) precursor protein (APP) transgenic mice.

An immunohistochemical study of the serotonin 1A receptor in the hippocampus of subjects with Alzheimer's disease

Alzheimer's disease (AD) is associated with neuronal degeneration, synaptic loss and deficits in multiple neurotransmitter systems. Alterations in the serotonin 1A (5‐HT1A) receptor can contribute to impaired cognitive function in AD, and both in vitro binding and Positron emission tomography (PET) imaging studies have demonstrated that 5‐HT1A receptors in the hippocampus/medial temporal cortex are affected early in AD. This neuropathological study examined the localization and immunoreaction intensity of 5‐HT1A receptor protein in AD hippocampus with the goal to determine whether neuronal receptor levels are influenced by the severity of NFT severity defined by Braaks' pathological staging and to provide immunohistochemical confirmation of the binding assays and PET imaging studies. Subjects included AD patients and non‐AD controls (NC) stratified into three Braaks' stages (Braak 0–II, NC; Braak III/IV and V/VI, AD). In the Braak 0–II group, 5‐HT1A‐immunoreactivity (ir) was prominent in the neuropil of the CA1 and subiculum, moderate in the dentate gyrus molecular layer (DGml), and low in the CA3 and CA4. No changes in 5‐HT1A‐ir were observed in the hippocampus of AD subjects in the Braak III/IV group. Hippocampal 5‐HT1A‐ir intensity was markedly decreased in the CA1 region in 6/11 (54.5%) subjects in the Braak V/VI group. Across all three groups combined, there was a statistically significant association between reduced 5HT1A‐ir and neuronal loss in the CA1, but not in the CA3. The present data demonstrate that hippocampal 5‐HT1A receptors are mainly preserved until the end‐stage of NFT progression in AD. Thus, the utility of PET imaging using a 5‐HT1A‐specific radiolabeled probe as a marker of hippocampal neuronal loss may be limited to the CA1 field in advanced stage AD cases.