Human iPSC-derived astrocytes transplanted into the mouse brain undergo morphological changes in response to amyloid-beta plaques

BACKGROUND: Increasing evidence for a direct contribution of astrocytes to neuroinflammatory and neurodegenerative processes causing Alzheimer’s disease comes from molecular and functional studies in rodent models. However, these models may not fully recapitulate human disease as human and rodent astrocytes differ considerably in morphology, functionality, and gene expression. RESULTS: To address these challenges, we established an approach to study human astrocytes within the mouse brain by transplanting human induced pluripotent stem cell (hiPSC)-derived astrocyte progenitors into neonatal brains. Xenografted hiPSC-derived astrocyte progenitors differentiated into astrocytes that integrated functionally within the mouse host brain and matured in a cell-autonomous way retaining human-specific morphologies, unique features, and physiological properties. In Alzheimer´s chimeric brains, transplanted hiPSC-derived astrocytes responded to the presence of amyloid plaques undergoing morphological changes that seemed independent of the APOE allelic background. CONCLUSIONS: In sum, we describe here a promising approach that consist of transplanting patient-derived and genetically modified astrocytes into the mouse brain to study human astrocyte pathophysiology in the context of Alzheimer´s disease

Tracing of temporo-entorhinal connections in the human brain: cognitively impaired argyrophilic grain disease cases show dendritic alterations but no axonal disconnection of temporo-entorhinal association neurons

Argyrophilic grain disease (AGD), a neurodegenerative disorder, is often associated with mild to moderate Alzheimer’s disease (AD)-related pathology. The development of dementia in AGD is associated with the extent of coexisting AD-related pathology. Therefore, the question arises whether the degenerative changes in the neuronal network of demented AGD-patients represent a distinct pattern or show similar changes of disconnection as considered for AD. We were able to apply DiI-tracing in two human autopsy cases with mild AD-related pathology (controls), in one AD-patient, in one non-demented patient with advanced AD-related pathology, and in three cognitively impaired AGD-patients. DiI-crystals were injected into the entorhinal cortex. Pyramidal neurons of layers III and V of the adjacent temporal neocortex (area 35) were retrogradely marked with the tracer and analyzed. The AD case did not exhibit any retrogradely labeled neurons in the temporal neocortex. In the non-demented case with advanced AD-related pathology, the number of traced neurons was reduced as compared to that in the two controls and in the three AGD cases. In contrast, all three cognitively impaired AGD cases exhibited labeled pyramidal neurons in area 35 in an almost similar number as in the controls. However, alterations in the dendritic tree were observed in the AGD cases. These results show the existence of temporo-entorhinal connections in the adult human brain similar to those reported in animal models. Furthermore, the present study based on seven cases is the first attempt to study changes in the neuronal network in a human tauopathy with targeted axonal tracing techniques. Our findings in three cognitively impaired AGD cases suggest that AGD-related dementia constitutes a distinct disorder with a characteristic pattern of degeneration in the neuronal network

Post-mortem histopathology underlying β-amyloid PET imaging following flutemetamol F 18 injection

In vivo imaging of fibrillar β-amyloid deposits may assist clinical diagnosis of Alzheimer's disease (AD), aid treatment selection for patients, assist clinical trials of therapeutic drugs through subject selection, and be used as an outcome measure. A recent phase III trial of [(18)F]flutemetamol positron emission tomography (PET) imaging in 106 end-of-life subjects demonstrated the ability to identify fibrillar β-amyloid by comparing in vivo PET to post-mortem histopathology. Post-mortem analyses demonstrated a broad and continuous spectrum of β-amyloid pathology in AD and other dementing and non-dementing disease groups. The GE067-026 trial demonstrated 91% sensitivity and 90% specificity of [(18)F]flutemetamol PET by majority read for the presence of moderate or frequent plaques. The probability of an abnormal [(18)F]flutemetamol scan increased with neocortical plaque density and AD diagnosis. All dementia cases with non-AD neurodegenerative diseases and those without histopathological features of β-amyloid deposits were [(18)F]flutemetamol negative. Majority PET assessments accurately reflected the amyloid plaque burden in 90% of cases. However, ten cases demonstrated a mismatch between PET image interpretations and post-mortem findings. Although tracer retention was best associated with amyloid in neuritic plaques, amyloid in diffuse plaques and cerebral amyloid angiopathy best explain three [(18)F]flutemetamol positive cases with mismatched (sparse) neuritic plaque burden. Advanced cortical atrophy was associated with the seven false negative [(18)F]flutemetamol images. The interpretation of images from pathologically equivocal cases was associated with low reader confidence and inter-reader agreement. Our results support that amyloid in neuritic plaque burden is the primary form of β-amyloid pathology detectable with [(18)F]flutemetamol PET imaging

Stages of granulovacuolar degeneration: their relation to Alzheimer's disease and chronic stress response

status: publishe

Apolipoprotein epsilon 3 alleles are associated with indicators of neuronal resilience

<p>Abstract</p> <p>Background</p> <p>Epilepsy is associated with precocious development of Alzheimer-type neuropathological changes, including appearance of senile plaques, neuronal loss and glial activation. As inheritance of <it>APOE ε4 </it>allele(s) is reported to favor this outcome, we sought to investigate neuronal and glial responses that differ according to <it>APOE </it>genotype. With an eye toward defining ways in which <it>APOE ε3 </it>alleles may foster neuronal well-being in epilepsy and/or <it>APOE ε4 </it>alleles exacerbate neuronal decline, neuronal and glial characteristics were studied in temporal lobectomy specimens from epilepsy patients of either <it>APOE ε4,4 </it>or <it>APOE ε3,3 </it>genotype.</p> <p>Methods</p> <p>Tissue and/or cellular expressions of interleukin-1 alpha (IL-1α), apolipoprotein E (ApoE), amyloid β (Aβ) precursor protein (βAPP), synaptophysin, phosphorylated tau, and Aβ were determined in frozen and paraffin-embedded tissues from 52 <it>APOE ε3,3 </it>and 7 <it>APOE ε4,4 </it>(0.25 to 71 years) epilepsy patients, and 5 neurologically normal patients using Western blot, RT-PCR, and fluorescence immunohistochemistry.</p> <p>Results</p> <p>Tissue levels of IL-1α were elevated in patients of both <it>APOE ε3,3 </it>and <it>APOE ε4,4 </it>genotypes, and this elevation was apparent as an increase in the number of activated microglia per neuron (<it>APOE </it>ε<it>3,3 </it>vs <it>APOE ε4,4 </it>= 3.7 ± 1.2 vs 1.5 ± 0.4; <it>P </it>< 0.05). This, together with increases in βAPP and ApoE, was associated with apparent neuronal sparing in that <it>APOE ε4,4 </it>genotype was associated with smaller neuron size (<it>APOE ε4,4 </it>vs <it>APOE ε3,3 </it>= 173 ± 27 vs 356 ± 45; <it>P </it>≤ 0.01) and greater DNA damage (<it>APOE ε4,4 </it>vs <it>APOE ε3,3 </it>= 67 ± 10 vs 39 ± 2; <it>P </it>= 0.01). 3) Aβ plaques were noted at early ages in our epilepsy patients, regardless of <it>APOE </it>genotype (<it>APOE ε4,4 </it>age 10; <it>APOE ε3,3 </it>age 17).</p> <p>Conclusions</p> <p>Our findings of neuronal and glial events, which correlate with lesser neuronal DNA damage and larger, more robust neurons in epilepsy patients of <it>APOE ε3,3 </it>genotype compared to <it>APOE ε4,4 </it>genotype carriers, are consistent with the idea that the <it>APOE </it>ε<it>3,3 </it>genotype better protects neurons subjected to the hyperexcitability of epilepsy and thus confers less risk of AD (Alzheimer's disease).</p> <p>Please see related article: <url>http://www.biomedcentral.com/1741-7015/10/36</url></p

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

Dysfunctions 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

Performance of [(18)F]flutemetamol amyloid imaging against the neuritic plaque component of CERAD and the current (2012) NIA-AA recommendations for the neuropathologic diagnosis of Alzheimer's disease

INTRODUCTION: Performance of the amyloid tracer [(18)F]flutemetamol was evaluated against three pathology standard of truth (SoT) measures including neuritic plaques (CERAD "original" and "modified" and the amyloid component of the 2012 NIA-AA guidelines). METHODS: After [(18)F]flutemetamol imaging, 106 end-of-life patients who died underwent postmortem brain examination for amyloid plaque load. Blinded positron emission tomography scan interpretations by five independent electronically trained readers were compared with pathology measures. RESULTS: By SoT, sensitivity and specificity of majority image interpretations were, respectively, 91.9% and 87.5% with "original CERAD," 90.8% and 90.0% with "modified CERAD," and 85.7% and 100% with the 2012 NIA-AA criteria. DISCUSSION: The high accuracy of either CERAD criteria suggests that [(18)F]flutemetamol predominantly reflects neuritic amyloid plaque density. However, the use of CERAD criteria as the SoT can result in some false-positive results because of the presence of diffuse plaques, which are accounted for when the positron emission tomography read is compared with the 2012 NIA-AA criteria