Dataset Information

Hippocampal Reduction of α-Synuclein via RNA Interference Improves Neuropathology in Alzheimer's Disease Mice.

ABSTRACT:

Background

Alzheimer's disease (AD) cases are often characterized by the pathological accumulation of α-synuclein (α-syn) in addition to amyloid-β (Aβ) and tau hallmarks. The role of α-syn has been extensively studied in synucleinopathy disorders, but less so in AD. Recent studies have shown that α-syn may also play a role in AD and its downregulation may be protective against the toxic effects of Aβ accumulation.

Objective

We hypothesized that selectively knocking down α-syn via RNA interference improves the neuropathological and biochemical findings in AD mice.

Methods

Here we used amyloid precursor protein transgenic (APP-Tg) mice to model AD and explore pathologic and behavioral phenotypes with knockdown of α-syn using RNA interference. We selectively reduced α-syn levels by stereotaxic bilateral injection of either LV-shRNA α-syn or LV-shRNA-luc (control) into the hippocampus of AD mice.

Results

We found that downregulation of α-syn results in significant reduction in the number of Aβ plaques. In addition, mice treated with LV-shRNA α-syn had amelioration of abnormal microglial activation (Iba1) and astrocytosis (GFAP) phenotypes in AD mice.

Conclusion

Our data suggests a novel link between Aβ and α-syn pathology as well as a new therapeutic angle for targeting AD.

SUBMITTER: Leitao ADG

PROVIDER: S-EPMC10578232 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

Hippocampal Reduction of α-Synuclein via RNA Interference Improves Neuropathology in Alzheimer's Disease Mice.

Leitão André D G ADG Spencer Brian B Sarsoza Floyd F Ngolab Jennifer J Amalraj Jessica J Masliah Eliezer E Wu Chengbiao C Rissman Robert A RA

Journal of Alzheimer's disease : JAD 20230101 1

<h4>Background</h4>Alzheimer's disease (AD) cases are often characterized by the pathological accumulation of α-synuclein (α-syn) in addition to amyloid-β (Aβ) and tau hallmarks. The role of α-syn has been extensively studied in synucleinopathy disorders, but less so in AD. Recent studies have shown that α-syn may also play a role in AD and its downregulation may be protective against the toxic effects of Aβ accumulation.<h4>Objective</h4>We hypothesized that selectively knocking down α-syn via ...[more]

PMID: 37522208

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Project description:α-Synuclein (αSN) in human is tightly linked both neuropathologically and genetically to Parkinson's disease (PD) and related disorders. Disease-causing properties in vivo of the wildtype mouse ortholog (mαSN), which carries a threonine at position 53 like the A53T human mutant version that is genetically linked to PD, were never reported. To this end we generated mouse lines that express mαSN in central neurons at levels reaching up to six-fold compared to endogenous mαSN. Unlike transgenic mice expressing human wildtype or mutant forms of αSN, these mαSN transgenic mice showed pronounced ubiquitin immunopathology in spinal cord and brainstem. Isoelectric separation of mαSN species revealed multiple isoforms including two Ser129-phosphorylated species in the most severely affected brain regions. Neuronal Ser129-phosphorylated αSN occurred in granular and small fibrillar aggregates and pathological staining patterns in neurites occasionally revealed a striking ladder of small alternating segments staining either for Ser129-phosphorylated αSN or ubiquitin but not both. Axonal degeneration in long white matter tracts of the spinal cord, with breakdown of myelin sheaths and degeneration of neuromuscular junctions with loss of integrity of the presynaptic neurofilament network in mαSN transgenic mice, was similar to what we have reported for mice expressing human αSN wildtype or mutant forms. In hippocampal neurons, the mαSN protein accumulated and was phosphorylated but these neurons showed no ubiquitin immunopathology. In contrast to the early-onset motor abnormalities and muscle weakness observed in mice expressing human αSN, mαSN transgenic mice displayed only end-stage phenotypic alterations that manifested alongside with neuropathology. Altogether these findings show that increased levels of wildtype mαSN does not induce early-onset behavior changes, but drives end-stage pathophysiological changes in murine neurons that are strikingly similar to those evoked by expression of human wildtype or mutant forms.

Project description:Misfolded α-synuclein protein accumulates in 43-63% of individuals with symptomatic Alzheimer's disease. Two main patterns of comorbid α-synuclein pathology have been identified: caudo-rostral and amygdala-predominant. α-Synuclein aggregates have been shown to interact with the transactive response DNA-binding protein 43 (TDP-43) and abnormally phosphorylated tau protein. All these proteins accumulate in the amygdala, which is anatomically connected with the hippocampus. However, the specific role of amygdala-predominant α-synuclein pathology in the progression of Alzheimer's disease and hippocampal degeneration remains unclear. In this cross-sectional study, we analysed 291 autopsy brains from both demented and non-demented elderly individuals neuropathologically. Neuronal density in the CA1 region of the hippocampus was assessed for all cases. We semiquantitatively evaluated α-synuclein pathology severity across seven brain regions and calculated a ratio of limbic to brainstem α-synuclein pathology severity, which was used to stratify the cases into two distinct spreading patterns. In the 99 symptomatic Alzheimer's disease cases, we assessed severity of limbic-predominant age-related TDP-43 neuropathological changes and CA1 phosphorylated tau density. We performed triple fluorescence staining of medial temporal lobe samples with antibodies against phosphorylated TDP-43, α-synuclein and phosphorylated tau. Finally, we employed path analysis to determine the association network of various parameters of limbic pathology in Alzheimer's disease cases and CA1 neuronal density. We identified an association between the amygdala-predominant αSyn pathology pattern and decreased neuronal density in the CA1 region. We found that Alzheimer's disease cases with an amygdala-predominant α-synuclein pattern exhibited the highest TDP-43 severity and prevalence of TDP-43 inclusions in the dentate gyrus among all groups, while those with the caudo-rostral pattern had the lowest severity of Alzheimer's disease neuropathological changes. We observed colocalization of TDP-43, aggregated α-synuclein and hyperphosphorylated tau in cytoplasmic inclusions within hippocampal and amygdala neurons of Alzheimer's disease cases. Path analysis modelling suggests that the relationship between amygdala-predominant α-synuclein pathology and CA1 neuron loss is partially mediated by hippocampal tau and TDP-43 aggregates. Our findings suggest that Alzheimer's disease cases with amygdala-predominant α-synuclein pathology may constitute a distinct group with more severe hippocampal damage, a higher TDP-43 burden and potential interactions among α-synuclein, TDP-43 and hyperphosphorylated tau.

Project description:α-Synuclein is the major pathological component of synucleinopathies including Parkinson's disease and dementia with Lewy bodies. Recent studies have demonstrated that α-synuclein also plays important roles in the release of synaptic vesicles and synaptic membrane recycling in healthy neurons. However, the precise relationship between the pathogenicity and physiological functions of α-synuclein remains to be elucidated. To address this issue, we investigated the subcellular localization of α-synuclein in normal and pathological conditions using primary mouse hippocampal neuronal cultures. While some neurons expressed high levels of α-synuclein in presynaptic boutons and cell bodies, other neurons either did not or only very weakly expressed the protein. These α-synuclein-negative cells were identified as inhibitory neurons by immunostaining with specific antibodies against glutamic acid decarboxylase (GAD), parvalbumin, and somatostatin. In contrast, α-synuclein-positive synapses were colocalized with the excitatory synapse marker vesicular glutamate transporter-1. This expression profile of α-synuclein was conserved in the hippocampus in vivo. In addition, we found that while presynaptic α-synuclein colocalizes with synapsin, a marker of presynaptic vesicles, it is not essential for activity-dependent membrane recycling induced by high potassium treatment. Exogenous supply of preformed fibrils generated by recombinant α-synuclein was shown to promote the formation of Lewy body (LB) -like intracellular aggregates involving endogenous α-synuclein. GAD-positive neurons did not form LB-like aggregates following treatment with preformed fibrils, however, exogenous expression of human α-synuclein allowed intracellular aggregate formation in these cells. These results suggest the presence of a different mechanism for regulation of the expression of α-synuclein between excitatory and inhibitory neurons. Furthermore, α-synuclein expression levels may determine the efficiency of intracellular aggregate formation in different neuronal subtypes.

Dataset Information

Hippocampal Reduction of α-Synuclein via RNA Interference Improves Neuropathology in Alzheimer's Disease Mice.

Background

Objective

Methods

Results

Conclusion

Publications

Hippocampal Reduction of α-Synuclein via RNA Interference Improves Neuropathology in Alzheimer's Disease Mice.

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