Seeding of protein aggregation causes cognitive impairment in rat model of cortical synucleinopathy

Abstract

A BS TRACT: Background: Cortical α-synuclein pathology plays a role in the development of cognitive dysfunction in both Parkinson's disease and dementia with Lewy bodies, although the causative cellular lesions have remained unclear. We aimed to address causal links between α-synuclein-driven pathology in the cerebral cortex and the development of cognitive impairments using new experimental models. Methods: Neuronal overexpression of human α-synuclein was induced in the rat medial prefrontal cortex using viral vectors. This was combined with inoculations of preformed fibrils of human α-synuclein in some animals. Rats were evaluated with tests probing prefrontal cognitive functions (delayed matching/nonmatching to position and 5-choice serial reaction time task). Patterns of neuropathology were characterized immunohistochemically. Results: Neither α-synuclein overexpression nor the fibril seeds alone yielded any behavioral phenotype. In contrast, combining the 2 approaches produced significant impairments in working memory, attention, and inhibitory control.All animals injected with α-synuclein vectors exhibited high immunoreactivity for human α-synuclein in the medial prefrontal cortex and its primary projection targets. However, only when this overexpression was combined with fibril inoculations did animals exhibit large, proteinase K-resistant and Ser 129 -phosphorylated α-synuclein intraneuronal inclusions in the medial prefrontal cortex and its closely interconnected brain regions. The inclusions were associated with distorted dendritic morphologies and partial neuronal loss in the targeted cortical areas. Conclusions: Cortical overexpression of human α-synuclein is not sufficient to produce cognitive dysfunction, whereas combining this overexpression with fibril seeds yields both cognitive and histopathological phenotypes that are relevant to human Lewy body disease.

Back and to the Future: From Neurotoxin‐Induced to Human Parkinson's Disease Models

“…() reported that combining PFFs with AAV‐mediated α‐synuclein overexpression in the SNpc results in more rapid development of Lewy body‐like pathology in rats, accompanied by dopaminergic neuron loss, decreased dopamine levels, and impaired motor behavior. AAV‐mediated overexpression of α‐synuclein in rat prefrontal cortex combined with PFFs seeding results in extensive α‐synuclein aggregation pathology and significant impairment of cognitive functions, such as memory, attention, and inhibitory control (Espa et al., ). Along with these studies, α‐synuclein pathology development was accelerated by combining AAV‐mediated α‐synuclein overexpression and α‐synuclein insoluble species (both fibrils and ribbons) inoculation in mice.…”

Structural basis of the interplay between α-synuclein and Tau in regulating pathological amyloid aggregation

“…Furthermore, animal studies showed that an injection of preformed α-syn fibrils in the mouse brain triggers Tau aggregation and pathology (14). In contrast, knockout of α-syn or Tau could effectively abolish the pathology induced by α-syn aggregation in animal models (15,16). Thus, α-syn and Tau may act synergistically to form a deleterious feed-forward loop in disease development.…”

Metabolomics Fingerprint Induced by the Intranigral Inoculation of Exogenous Human Alpha-Synuclein Oligomers in a Rat Model of Parkinson’s Disease

“…The intracerebral inoculation of preformed αSyn fibrils and oligomers is increasingly used as a preclinical model of PD [10][11][12][13][14][15]. Indeed, the presence of soluble oligomers in affected brain areas [38] and biological fluids of PD patients [3,4], suggested the pathological role of oligomeric species of αSyn.…”

“…α-Syn neurotoxicity has defined the rationale for αSyn-based preclinical models of PD [8,9] and, in recent years, the intracerebral inoculation of preformed αSyn fibrils and oligomers has been proposed as a significant disease model [10][11][12][13][14][15]. Lately, preformed αSyn oligomers of human origin (HαSynO) have been produced and characterized for their in vitro and in vivo toxicity in neurons [7,16].…”

“…The aim of the present work was to evaluate the metabolic profile of brain tissue and serum samples of rats inoculated with preformed HαSynOs into the substantia nigra pars compacta (SNpc) [10,11]. Given the human origin of the inoculated oligomers, and since this model reproduces neuropathological mechanisms of PD, we investigated whether it may offer a tool to model the metabolic fingerprint of PD.…”