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MGluR5 Contribution to Neuropathology in Alzheimer Mice Is Disease Stage-Dependent.

ABSTRACT: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and is characterized by a progressive cognitive decline in affected individuals. Current therapeutic strategies are limited in their efficacy and some have proven to be even less effective at later disease stages or after extended use. We previously demonstrated that chronic inhibition of mGluR5 signaling using the selective negative allosteric modulator (NAM) CTEP in APPswe/PS1?E9 mice can rescue cognitive function, activating the ZBTB16-mediated autophagy pathway to reduce A?, the principal neurotoxic species in AD brains. Here, we evaluated the efficacy of long-term treatment with CTEP in 6 month old APPswe/PS1?E9 mice for either 24 or 36 weeks. CTEP maintained its efficacy in reversing working and spatial memory deficits and mitigating neurogliosis in APPswe/PS1?E9 mice when administered for 24 weeks. This was paralleled by a significant reduction in A? oligomer and plaque load as a result of autophagy activation via ZBTB16 and mTOR-dependent pathways. However, further extension of CTEP treatment for 36 weeks was found ineffective in reversing memory deficit, neurogliosis, or A?-related pathology. We found that this loss in CTEP efficacy in 15 month old APPswe/PS1?E9 mice was due to the abolished contribution of ZBTB16 and mTOR-mediated signaling to AD neuropathology at this advanced disease stage. Our findings indicate that the contribution of pathological mGluR5-signaling to AD may shift as the disease progresses. Thus, we provide the first evidence that the underlying pathophysiological mechanism(s) of AD may unfold along the course of the disease and treatment strategies should be modified accordingly to ensure maximal therapeutic outcomes.

SUBMITTER: Abd-Elrahman KS

PROVIDER: S-EPMC7155195 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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mGluR5 Contribution to Neuropathology in Alzheimer Mice Is Disease Stage-Dependent.

Abd-Elrahman Khaled S KS Hamilton Alison A Albaker Awatif A Ferguson Stephen S G SSG

ACS pharmacology & translational science 20200312 2

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and is characterized by a progressive cognitive decline in affected individuals. Current therapeutic strategies are limited in their efficacy and some have proven to be even less effective at later disease stages or after extended use. We previously demonstrated that chronic inhibition of mGluR5 signaling using the selective negative allosteric modulator (NAM) CTEP in APPswe/PS1ΔE9 mice can rescue cognitive function, activa ...[more]

PMID: 32296772

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Project description:Animal models aim to replicate the symptoms, the lesions or the cause(s) of Alzheimer disease. Numerous mouse transgenic lines have now succeeded in partially reproducing its lesions: the extracellular deposits of Abeta peptide and the intracellular accumulation of tau protein. Mutated human APP transgenes result in the deposition of Abeta peptide, similar but not identical to the Abeta peptide of human senile plaque. Amyloid angiopathy is common. Besides the deposition of Abeta, axon dystrophy and alteration of dendrites have been observed. All of the mutations cause an increase in Abeta 42 levels, except for the Arctic mutation, which alters the Abeta sequence itself. Overexpressing wild-type APP alone (as in the murine models of human trisomy 21) causes no Abeta deposition in most mouse lines. Doubly (APP x mutated PS1) transgenic mice develop the lesions earlier. Transgenic mice in which BACE1 has been knocked out or overexpressed have been produced, as well as lines with altered expression of neprilysin, the main degrading enzyme of Abeta. The APP transgenic mice have raised new questions concerning the mechanisms of neuronal loss, the accumulation of Abeta in the cell body of the neurons, inflammation and gliosis, and the dendritic alterations. They have allowed some insight to be gained into the kinetics of the changes. The connection between the symptoms, the lesions and the increase in Abeta oligomers has been found to be difficult to unravel. Neurofibrillary tangles are only found in mouse lines that overexpress mutated tau or human tau on a murine tau -/- background. A triply transgenic model (mutated APP, PS1 and tau) recapitulates the alterations seen in AD but its physiological relevance may be discussed. A number of modulators of Abeta or of tau accumulation have been tested. A transgenic model may be analyzed at three levels at least (symptoms, lesions, cause of the disease), and a reading key is proposed to summarize this analysis.

Project description:Importance:Social determinants of health, such as income, education, housing quality, and employment, are associated with disparities in Alzheimer disease and health generally, yet these determinants are rarely incorporated within neuropathology research. Objective:To establish the feasibility of linking neuropathology data to social determinants of health exposures using neighborhood disadvantage metrics (the validated Area Deprivation Index) and to evaluate the association between neighborhood disadvantage and Alzheimer disease-related neuropathology. Design, Setting, and Participants:This cross-sectional study consisted of decedents with a known home address who donated their brains to 1 of 2 Alzheimer disease research center brain banks in California and Wisconsin between January 1, 1990, and December 31, 2016. Neither site had preexisting social metrics available for their decedents. Neuropathologic features were obtained from each site for data collected using the standardized Neuropathology Data Set form and from autopsy reports. Data were analyzed from June 7 to October 10, 2019. Exposures:Geocoded decedent addresses linked to neighborhood disadvantage as measured by the Area Deprivation Index calculated for the year of death. Main Outcomes and Measures:Presence of Alzheimer disease neuropathology. The association between neighborhood disadvantage and Alzheimer disease neuropathology was evaluated via logistic regression, adjusting for age, sex, and year of death. Results:The sample consisted of 447 decedents (249 men [56%]; mean [SD] age, 80.3 [9.5] years; median year of death, 2011) spanning 24 years of donation. Fewer decedents (n?=?24 [5.4%]) originated from the top 20% most disadvantaged neighborhood contexts. Increasing neighborhood disadvantage was associated with an 8.1% increase in the odds of Alzheimer disease neuropathology for every decile change on the Area Deprivation Index (adjusted odds ratio, 1.08; 95% CI, 1.07-1.09). As such, living in the most disadvantaged neighborhood decile was associated with a 2.18 increased odds of Alzheimer disease neuropathology (adjusted odds ratio, 2.18; 95% CI, 1.99-2.39). Conclusions and Relevance:The findings of this cross-sectional study suggest that social determinants of health data can be linked to preexisting autopsy samples as a means to study sociobiological mechanisms involved in neuropathology. This novel technique has the potential to be applied to any brain bank within the United States. To our knowledge, this is the first time Alzheimer disease neuropathology has been associated with neighborhood disadvantage.

Project description:BACKGROUND: Alzheimer's disease (AD) is the most prevalent form of age-related dementia, and its effect on society increases exponentially as the population ages. Accumulating evidence suggests that neuroinflammation, mediated by the brain's innate immune system, contributes to AD neuropathology and exacerbates the course of the disease. However, there is no experimental evidence for a causal link between systemic inflammation or neuroinflammation and the onset of the disease. METHODS: The viral mimic, polyriboinosinic-polyribocytidilic acid (PolyI:C) was used to stimulate the immune system of experimental animals. Wild-type (WT) and transgenic mice were exposed to this cytokine inducer prenatally (gestation day (GD)17) and/or in adulthood. Behavioral, immunological, immunohistochemical, and biochemical analyses of AD-associated neuropathologic changes were performed during aging. RESULTS: We found that a systemic immune challenge during late gestation predisposes WT mice to develop AD-like neuropathology during the course of aging. They display chronic elevation of inflammatory cytokines, an increase in the levels of hippocampal amyloid precursor protein (APP) and its proteolytic fragments, altered Tau phosphorylation, and mis-sorting to somatodendritic compartments, and significant impairments in working memory in old age. If this prenatal infection is followed by a second immune challenge in adulthood, the phenotype is strongly exacerbated, and mimics AD-like neuropathologic changes. These include deposition of APP and its proteolytic fragments, along with Tau aggregation, microglia activation and reactive gliosis. Whereas A? peptides were not significantly enriched in extracellular deposits of double immune-challenged WT mice at 15 months, they dramatically increased in age-matched immune-challenged transgenic AD mice, precisely around the inflammation-induced accumulations of APP and its proteolytic fragments, in striking similarity to the post-mortem findings in human patients with AD. CONCLUSION: Chronic inflammatory conditions induce age-associated development of an AD-like phenotype in WT mice, including the induction of APP accumulations, which represent a seed for deposition of aggregation-prone peptides. The PolyI:C mouse model therefore provides a unique tool to investigate the molecular mechanisms underlying the earliest pathophysiological changes preceding fibrillary A? plaque deposition and neurofibrillary tangle formations in a physiological context of aging. Based on the similarity between the changes in immune-challenged mice and the development of AD in humans, we suggest that systemic infections represent a major risk factor for the development of AD.

Project description:Amyloid beta (Aβ) plaque is a defining pathologic feature of Alzheimer disease (AD). Aducanumab, a monoclonal IgG1 that selectively binds aggregated species of Aβ, has been shown by amyloid positron emission tomography (Amyloid PET) to reduce Aβ plaques in patients with prodromal and mild AD. This is the first autopsy report of the AD neuropathology in a patient previously treated with aducanumab. The patient was an 84-year-old woman who was randomized to the placebo arm of the PRIME Phase 1b study (221AD103). The patient progressed to moderate dementia (MMSE = 14/30), beyond the targeted early AD treatment stage, before receiving aducanumab in the long-term extension (LTE). The patient then received 32 monthly doses of aducanumab, titrated up to 6 mg/kg, for a cumulative dose of 186 mg/kg. In the LTE, Amyloid PET scans demonstrated robust Aβ plaque reduction, from a composite standard uptake value ratio (SUVR) of 1.5 at screening to < 1.1 at 56 weeks post-aducanumab dosing. MRI examinations were negative for amyloid-related imaging abnormalities (ARIA). She passed away in hospice care 4 months after her last dose of aducanumab. The postmortem neuropathologic examination confirmed AD neuropathologic changes. Aβ and IBA1 immunohistochemistry assays demonstrated sparse residual Aβ plaque engaged by amoeboid reactive microglia. Phospho-Tau (pTau) immunohistochemistry demonstrated neocortical neurofibrillary degeneration (Braak stage V, NIA/AA Stage B3). However, the density of pTau neuropathology, including neuritic plaque pTau (NP-Tau), appeared lower in the PRIME LTE Patient compared to a reference cohort of untreated Braak stage V-VI, NIA/AA Stage B3 AD cases. Taken together, this case report is the first to provide Amyloid PET and neuropathologic evidence substantiating the impact of aducanumab to reduce Aβ plaque neuropathology in a patient with AD. Furthermore, this report underscores the critical importance of autopsy neuropathology studies to augment our understanding of aducanumab's mechanism of action and impact on AD biomarkers.

Dataset Information

MGluR5 Contribution to Neuropathology in Alzheimer Mice Is Disease Stage-Dependent.

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mGluR5 Contribution to Neuropathology in Alzheimer Mice Is Disease Stage-Dependent.

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