Developmental deficits and staging of dynamics of age associated Alzheimer’s disease neurodegeneration and neuronal loss in subjects with Down syndrome

AbstractThe increased life expectancy of individuals with Down syndrome (DS) is associated with increased prevalence of trisomy 21–linked early-onset Alzheimer’s disease (EOAD) and dementia. The aims of this study of 14 brain regions including the entorhinal cortex, hippocampus, basal ganglia, and cerebellum in 33 adults with DS 26–72 years of age were to identify the magnitude of brain region–specific developmental neuronal deficits contributing to intellectual deficits, to apply this baseline to identification of the topography and magnitude of neurodegeneration and neuronal and volume losses caused by EOAD, and to establish age-based staging of the pattern of genetically driven neuropathology in DS. Both DS subject age and stage of dementia, themselves very strongly correlated, were strong predictors of an AD-associated decrease of the number of neurons, considered a major contributor to dementia. The DS cohort was subclassified by age as pre-AD stage, with 26–41-year-old subjects with a full spectrum of developmental deficit but with very limited incipient AD pathology, and 43–49, 51–59, and 61–72-year-old groups with predominant prevalence of mild, moderately severe, and severe dementia respectively. This multiregional study revealed a 28.1% developmental neuronal deficit in DS subjects 26–41 years of age and 11.9% AD-associated neuronal loss in DS subjects 43–49 years of age; a 28.0% maximum neuronal loss at 51–59 years of age; and a 11.0% minimum neuronal loss at 61–72 years of age. A total developmental neuronal deficit of 40.8 million neurons and AD-associated neuronal loss of 41.6 million neurons reflect a comparable magnitude of developmental neuronal deficit contributing to intellectual deficits, and AD-associated neuronal loss contributing to dementia. This highly predictable pattern of pathology indicates that successful treatment of DS subjects in the fourth decade of life may prevent AD pathology and functional decline.

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Learning Deficits Accompanied by Microglial Proliferation After the Long-Term Post-Injection of Alzheimer’s Disease Brain Extract in Mouse Brains

Journal of Alzheimer s Disease ◽

10.3233/jad-201002 ◽

2021 ◽

Vol 79 (4) ◽

pp. 1701-1711

Author(s):

Tetsuo Hayashi ◽

Shotaro Shimonaka ◽

Montasir Elahi ◽

Shin-Ei Matsumoto ◽

Koichi Ishiguro ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Brain ◽

Functional Decline ◽

Brain Regions ◽

Insoluble Fraction ◽

Brain Extract ◽

Post Injection ◽

Learning Deficits

Background: Human tauopathy brain injections into the mouse brain induce the development of tau aggregates, which spread to functionally connected brain regions; however, the features of this neurotoxicity remain unclear. One reason may be short observational periods because previous studies mostly used mutated-tau transgenic mice and needed to complete the study before these mice developed neurofibrillary tangles. Objective: To examine whether long-term incubation of Alzheimer’s disease (AD) brain in the mouse brain cause functional decline. Methods: We herein used Tg601 mice, which overexpress wild-type human tau, and non-transgenic littermates (NTg) and injected an insoluble fraction of the AD brain into the unilateral hippocampus. Results: After a long-term (17–19 months) post-injection, mice exhibited learning deficits detected by the Barnes maze test. Aggregated tau pathology in the bilateral hippocampus was more prominent in Tg601 mice than in NTg mice. No significant changes were observed in the number of Neu-N positive cells or astrocytes in the hippocampus, whereas that of Iba-I-positive microglia increased after the AD brain injection. Conclusion: These results potentially implicate tau propagation in functional decline and indicate that long-term changes in non-mutated tau mice may reflect human pathological conditions.

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Defining early changes in Alzheimer’s disease from RNA sequencing of brain regions differentially affected by pathology

Scientific Reports ◽

10.1038/s41598-021-83872-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Boris Guennewig ◽

Julia Lim ◽

Lee Marshall ◽

Andrew N. McCorkindale ◽

Patrick J. Paasila ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rna Sequencing ◽

Neuronal Loss ◽

Brain Regions ◽

Post Mortem ◽

Tau Pathology ◽

Membrane Spanning ◽

Immune Related Genes ◽

Vesicle Secretion

AbstractTau pathology in Alzheimer’s disease (AD) spreads in a predictable pattern that corresponds with disease symptoms and severity. At post-mortem there are cortical regions that range from mildly to severely affected by tau pathology and neuronal loss. A comparison of the molecular signatures of these differentially affected areas within cases and between cases and controls may allow the temporal modelling of disease progression. Here we used RNA sequencing to explore differential gene expression in the mildly affected primary visual cortex and moderately affected precuneus of ten age-, gender- and RNA quality-matched post-mortem brains from AD patients and healthy controls. The two regions in AD cases had similar transcriptomic signatures but there were broader abnormalities in the precuneus consistent with the greater tau load. Both regions were characterised by upregulation of immune-related genes such as those encoding triggering receptor expressed on myeloid cells 2 and membrane spanning 4-domains A6A and milder changes in insulin/IGF1 signalling. The precuneus in AD was also characterised by changes in vesicle secretion and downregulation of the interneuronal subtype marker, somatostatin. The ‘early’ AD transcriptome is characterised by perturbations in synaptic vesicle secretion on a background of neuroimmune dysfunction. In particular, the synaptic deficits that characterise AD may begin with the somatostatin division of inhibitory neurotransmission.

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Ceramide and Related-Sphingolipid Levels Are Not Altered in Disease-Associated Brain Regions of APPSLand APPSL/PS1M146LMouse Models of Alzheimer's Disease: Relationship with the Lack of Neurodegeneration?

International Journal of Alzheimer s Disease ◽

10.4061/2011/920958 ◽

2011 ◽

Vol 2011 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Laurence Barrier ◽

Bernard Fauconneau ◽

Anastasia Noël ◽

Sabrina Ingrand

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Animal Models ◽

Neuronal Death ◽

Time Course ◽

Neuronal Loss ◽

Brain Regions ◽

App Processing ◽

Ceramide Accumulation ◽

The Brain

There is evidence linking sphingolipid abnormalities, APP processing, and neuronal death in Alzheimer's disease (AD). We previously reported a strong elevation of ceramide levels in the brain of the APPSL/PS1Ki mouse model of AD, preceding the neuronal death. To extend these findings, we analyzed ceramide and related-sphingolipid contents in brain from two other mouse models (i.e., APPSLand APPSL/PS1M146L) in which the time-course of pathology is closer to that seen in most currently available models. Conversely to our previous work, ceramides did not accumulate in disease-associated brain regions (cortex and hippocampus) from both models. However, the APPSL/PS1Ki model is unique for its drastic neuronal loss coinciding with strong accumulation of neurotoxic Aβisoforms, not observed in other animal models of AD. Since there are neither neuronal loss nor toxic Aβspecies accumulation in APPSLmice, we hypothesized that it might explain the lack of ceramide accumulation, at least in this model.

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Genetic analyses of SERPINA5 in Alzheimer’s disease

10.21203/rs.3.rs-769744/v1 ◽

2021 ◽

Author(s):

Billie J. Matchett ◽

Sarah J. Lincoln ◽

Matt Baker ◽

Nikoleta Tamvaka ◽

Janisse Cabrera-Rodriguez ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Disease Duration ◽

Age Of Onset ◽

Positive Family History ◽

Neuronal Loss ◽

Missense Variant ◽

Brain Regions ◽

Allelic Frequency ◽

Genomic Databases

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is the most common cause of dementia. Our previous studies have shown that increased expression of the SERPINA5 gene is associated with hippocampal vulnerability in AD, and that the SERPINA5 protein binds to tau and co-localizes within neurofibrillary tangles. To determine if genetic variants in the SERPINA5 gene may be contributing to this phenotype, we sequenced 103 autopsy-confirmed young-onset AD cases with a positive family history of cognitive decline. We observed one individual with a rare missense variant (rs140138746) in the SERPINA5 gene, resulting in an amino acid change (p.E228Q). We screened a further 1170 neuropathologically diagnosed AD cases and identified an additional 5 carriers of this variant, resulting in an allelic frequency of 0.002141 within our AD validation cohort, which was comparable to online genomic databases. Although not significant, SERPINA5 p.E228Q variant carriers were found to be younger at age of onset and age of death than non-carriers. SERPINA5 p.E228Q variant carriers had a longer disease duration than non-carriers, which approached significance. To further elucidate possible neuropathologic contributions of the SERPINA5 p.E228Q variant, we carried out descriptive neuropathologic burden analysis on a variant carrier that was matched to a non-carrier for age, sex, disease duration, Braak tangle stage, TDP-43 positive status, and who possessed an APOE ε4 risk allele. Interestingly, SERPINA5 burden was lower in the SERPINA5 p.E228Q carrier than the non-carrier in 9 corticolimbic brain regions studied, which exaggerated the tau:SERPINA5 immunohistochemical ratio. The SERPINA5 p.E228Q carrier was observed to have more severe neuronal loss in several brain regions compared to the non-carrier. Together, we cautiously interpret these findings to suggest that the SERPINA5 p.E228Q variant may stall tangle maturity and slow AD disease progression, thus prolonging disease duration in these individuals.

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Spatiotemporal activation of the C/EBPβ/δ-secretase axis regulates the pathogenesis of Alzheimer’s disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1815915115 ◽

2018 ◽

Vol 115 (52) ◽

pp. E12427-E12434 ◽

Cited By ~ 6

Author(s):

Hualong Wang ◽

Xia Liu ◽

Shengdi Chen ◽

Keqiang Ye

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Senile Plaques ◽

Neuronal Loss ◽

Brain Regions ◽

Dependent Manner ◽

Chronic Neuroinflammation ◽

Factor C ◽

The Brain ◽

Ad Mouse Model

Alzheimer’s disease (AD) neuropathological hallmarks include senile plaques with aggregated amyloid beta as a major component, neurofibrillary tangles (NFT) containing truncated and hyperphosphorylated Tau, extensive neuronal loss, and chronic neuroinflammation. However, the key molecular mechanism that dominates the pathogenesis of AD remains elusive for AD. Here we show that the C/EBPβ/δ-secretase axis is activated in an age-dependent manner in different brain regions of the 3×Tg AD mouse model, elevating δ-secretase–truncated APP and Tau proteolytic truncates and promoting senile plaques and NFT formation in the brain, associated with gradual neuronal loss and chronic neuroinflammation. Depletion of inflammatory cytokine-regulated transcription factor C/EBPβ from 3×Tg mice represses APP, Tau, and δ-secretase expression, which subsequently inhibits APP and Tau cleavage, leading to mitigation of AD pathologies. Knockout of δ-secretase from 3×Tg mice strongly blunts AD pathogenesis. Consequently, inactivation of the C/EBPβ/δ-secretase axis ameliorates cognitive dysfunctions in 3×Tg mice by blocking APP and Tau expression and their pathological fragmentation. Thus, our findings support the notion that C/EBPβ/δ-secretase axis plays a crucial role in AD pathogenesis.

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Psychotic Symptoms in Alzheimer's Disease Are Not Associated With More Severe Neuropathologic Features

International Psychogeriatrics ◽

10.1017/s1041610200006657 ◽

2000 ◽

Vol 12 (4) ◽

pp. 547-558 ◽

Cited By ~ 38

Author(s):

Robert A. Sweet ◽

Ronald L. Hamilton ◽

Oscar L. Lopez ◽

William E. Klunk ◽

Stephen R. Wisniewski ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Functional Decline ◽

Neurofibrillary Tangle ◽

Temporal Cortex ◽

Lewy Bodies ◽

Occipital Cortex ◽

Brain Regions ◽

Neuritic Plaque ◽

Psychotic Symptoms

Psychotic symptoms in Alzheimer's disease (AD) have been associated with increased rates of cognitive impairment and functional decline. Prior studies have been conflicting with regard to whether AD patients with psychosis (AD+P) have evidence of more severe neuropathologic findings at postmortem exam. We examined the severity of neuritic plaques and neurofibrillary tangles in six brain regions—middle frontal cortex, hippocampus, inferior parietal cortex, superior temporal cortex, occipital cortex, and transentorhinal cortex—in 24 AD+P subjects and 25 matched AD subjects without psychosis (AD-P). All analyses controlled for the presence of cortical Lewy bodies, and corrected for multiple comparisons. We found no significant associations between neuritic plaque and neurofibrillary tangle severity and AD+P, and no significant associations with any individual psychotic symptom. The association of AD+P with a more rapidly progressive course of AD appears to be mediated by a neuropathologic process other than increased severity of plaque and tangle formation.

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Molecular Networks and Key Regulators of the Dysregulated Neuronal System in Alzheimer’s Disease

10.1101/788323 ◽

2019 ◽

Cited By ~ 1

Author(s):

Minghui Wang ◽

Aiqun Li ◽

Michiko Sekiya ◽

Noam D. Beckmann ◽

Xiuming Quan ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Late Onset ◽

Brain Regions ◽

Molecular Networks ◽

Parahippocampal Gyrus ◽

Specific Gene ◽

Neuronal System ◽

Full Spectrum

SUMMARYTo study the molecular mechanisms driving the pathogenesis and identify novel therapeutic targets of late onset Alzheimer’s Disease (LOAD), we performed an integrative network analysis of whole-genome DNA and RNA sequencing profiling of four cortical areas, including the parahippocampal gyrus, across 364 donors spanning the full spectrum of LOAD-related cognitive and neuropathological disease severities. Our analyses revealed thousands of molecular changes and uncovered for the first-time multiple neuron specific gene subnetworks most dysregulated in LOAD. ATP6V1A, a critical subunit of vacuolar-type H+-ATPase (v-ATPase), was predicted to be a key regulator of one neuronal subnetwork and its role in disease-related processes was evaluated through CRISPR-based manipulation of human induced pluripotent stem cell derived neurons and RNAi-based knockdown in transgenic Drosophila models. This study advances our understanding of LOAD pathogenesis by providing the global landscape and detailed circuits of complex molecular interactions and regulations in several key brain regions affected by LOAD and the resulting network models provide a blueprint for developing next generation therapeutics against LOAD.

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Amyloid-beta, p-tau, and reactive microglia load are correlates of MRI cortical atrophy in Alzheimer's disease

10.1101/2021.06.16.448650 ◽

2021 ◽

Author(s):

Irene Frigerio ◽

Baayla DC Boon ◽

Chen-Pei Lin ◽

Yvon Galis-de Graaf ◽

John GJM Bol ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cortical Thickness ◽

Amyloid Beta ◽

Brain Regions ◽

Cortical Atrophy ◽

Strongly Correlated ◽

Phosphorylated Tau ◽

Post Mortem ◽

Reactive Microglia

INTRODUCTION: The aim of this study was to identify the histopathological correlates of MRI cortical atrophy in (a)typical Alzheimer's disease (AD) donors. METHODS: 19 AD and 10 control donors underwent post-mortem in-situ 3T-3DT1-MRI, from which cortical thickness was calculated. Upon subsequent autopsy, 21 cortical brain regions were selected and immunostained for amyloid-beta, phosphorylated-tau, and reactive microglia. MRI-pathology associations were assessed using linear mixed models. Post-mortem MRI was compared to ante-mortem MRI when available. RESULTS: Higher amyloid-beta load weakly correlated with a higher cortical thickness globally. Phosphorylated-tau strongly correlated with cortical atrophy in temporo-frontal regions. Reactive microglia load strongly correlated with cortical atrophy in the parietal region. Post-mortem scans showed high concordance with ante-mortem scans acquired <1 year before death. DISCUSSION: Distinct histopathological markers differently correlate with cortical atrophy, highlighting their different roles in the neurodegenerative process. This study contributes in understanding the pathological underpinnings of MRI atrophy patterns.

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Molecular characterization of selectively vulnerable neurons in Alzheimer’s Disease

10.1101/2020.04.04.025825 ◽

2020 ◽

Cited By ~ 5

Author(s):

Kun Leng ◽

Emmy Li ◽

Rana Eser ◽

Antonia Piergies ◽

Rene Sit ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Entorhinal Cortex ◽

Neuronal Loss ◽

Selective Vulnerability ◽

Brain Regions ◽

Neuronal Populations ◽

Expression Of Genes ◽

Single Nucleus

ABSTRACTAlzheimer’s disease (AD) is characterized by the selective vulnerability of specific neuronal populations, the molecular signatures of which are largely unknown. To identify and characterize selectively vulnerable neuronal populations, we used single-nucleus RNA sequencing to profile the caudal entorhinal cortex and the superior frontal gyrus – brain regions where neurofibrillary inclusions and neuronal loss occur early and late in AD, respectively – from postmortem brains spanning the progression of AD-type tau neurofibrillary pathology. We identified RORB as a marker of selectively vulnerable excitatory neurons in the entorhinal cortex, and subsequently validated their depletion and selective susceptibility to neurofibrillary inclusions during disease progression using quantitative neuropathological methods. We also discovered an astrocyte subpopulation, likely representing reactive astrocytes, characterized by decreased expression of genes involved in homeostatic functions. Our characterization of selectively vulnerable neurons in AD paves the way for future mechanistic studies of selective vulnerability and potential therapeutic strategies for enhancing neuronal resilience.

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Tau-induced focal neurotoxicity and network disruption related to apathy in Alzheimer’s disease

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-317970 ◽

2018 ◽

Vol 89 (11) ◽

pp. 1208-1214 ◽

Cited By ~ 8

Author(s):

Soichiro Kitamura ◽

Hitoshi Shimada ◽

Fumitoshi Niwa ◽

Hironobu Endo ◽

Hitoshi Shinotoh ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Diffusion Tensor ◽

Amyloid Β ◽

Neuronal Loss ◽

Brain Regions ◽

Subsequent Decrease ◽

Positron Emission ◽

Significant Difference ◽

Network Disruption

ObjectiveApathy is a common neuropsychological symptom in Alzheimer’s disease (AD), and previous studies demonstrated that neuronal loss and network disruption in some brain regions play pivotal roles in the pathogenesis of apathy. However, contributions of tau and amyloid-β (Aβ) depositions, pathological hallmarks of AD, to the manifestation of apathy remain elusive.MethodsSeventeen patients with AD underwent positron emission tomography (PET) with11C-pyridinyl-butadienyl-benzothiazole 3 (11C-PBB3) and11C-Pittsburgh compound-B (11C-PiB) to estimate tau and Aβ accumulations using standardised uptake value ratio (SUVR) images.11C-PBB3 and11C-PiB SUVR were compared between AD patients with high and low Apathy Scale (AS) scores. Additionally, volumetric and diffusion tensor MRI was performed in those areas where any significant difference was observed in PET analyses. Correlation and path analyses among AS and estimated imaging parameters were also conducted.ResultsAD patients with high AS scores showed higher11C-PBB3 SUVR in the orbitofrontal cortex (OFC) than those with low AS scores, while11C-PiB SUVR in any brain regions did not differ between them. Elevated11C-PBB3 SUVR in OFC, decreased OFC thickness and decreased fractional anisotropy (FA) in the uncinate fasciculus (UNC), which is structurally connected to OFC, correlated significantly with increased scores of the AS. Path analysis indicated that increased11C-PBB3 SUVR in OFC affects apathy directly and through reduction of OFC thickness and subsequent decrease of FA in UNC.ConclusionsThe present findings suggested that tau pathology in OFC may provoke focal neurotoxicity in OFC and the following disruption of the OFC-UNC network, leading to the emergence and progression of apathy in AD.

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