APPswe/PS1dE9/Blg Transgenic Mouse Line for Modeling Cerebral Amyloid Angiopathy Associated with Alzheimer’s Disease

Molecular Biology - Alzheimer’s disease (AD) is the most common proteinopathy, which is accompanied by a steady decrease in the patient’s cognitive functions with a simultaneous...     

Comparative Analysis of MPTP Neurotoxicity in Mice with a Constitutive Knockout of the α-Synuclein Gene

Molecular Biology - Aggregated forms of α-synuclein are core components of pathohistological inclusions known as Lewy bodies in substantia nigra (SN) neurons of patients with Parkinson’s...     

Behavioural impairments in mice of a novel FUS transgenic line recapitulate features of frontotemporal lobar degeneration

Multiple clinical and experimental evidences suggest that amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are members of a disease continuum. Pathological inclusions of fused in sarcoma (FUS) protein have been observed in subsets of patients with these diseases but their anatomical distribution is different for two diseases. These structures are present in motor neurons in ALS cases but in cortical neurons in FTLD cases. Expression of a C‐terminally truncated form of human FUS causes an early onset and progressive motor neuron pathology in transgenic mice but only when these neurons express a certain level of this protein. Severe motor dysfunction and early lethality of mice with expression above this level prevent their use for studies of FTLD‐related pathology caused by expression of this form of FUS. In the present study, we used another line of mice expressing the same protein but not developing any signs of motor system dysfunction due to substantially lower level of transgene expression in motor neurons. In a set of tests 5‐month old mice displayed certain behavioural abnormalities, including increased impulsivity, decreased anxiety and compromised social interaction, which recapitulate behaviour characteristics typically seen in FTLD patients.     

Molecular and behavioural abnormalities in the FUS‐tg mice mimic frontotemporal lobar degeneration: Effects of old and new anti‐inflammatory therapies

Genetic mutations in FUS, a DNA/RNA‐binding protein, are associated with inherited forms of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). A novel transgenic FUS[1‐359]‐tg mouse line recapitulates core hallmarks of human ALS in the spinal cord, including neuroinflammation and neurodegeneration, ensuing muscle atrophy and paralysis, as well as brain pathomorphological signs of FTLD. However, a question whether FUS[1‐359]‐tg mouse displays behavioural and brain pro‐inflammatory changes characteristic for the FTLD syndrome was not addressed. Here, we studied emotional, social and cognitive behaviours, brain markers of inflammation and plasticity of pre‐symptomatic FUS[1‐359]‐tg male mice, a potential FTLD model. These animals displayed aberrant behaviours and altered brain expression of inflammatory markers and related pathways that are reminiscent to the FTLD‐like syndrome. FTLD‐related behavioural and molecular Journal of Cellular and Molecular Medicine features were studied in the pre‐symptomatic FUS[1‐359]‐tg mice that received standard or new ALS treatments, which have been reported to counteract the ALS‐like syndrome in the mutants. We used anti‐ALS drug riluzole (8 mg/kg/d), or anti‐inflammatory drug, a selective blocker of cyclooxygenase‐2 (celecoxib, 30 mg/kg/d) for 3 weeks, or a single intracerebroventricular (i.c.v.) infusion of human stem cells (Neuro‐Cells, 500 000‐CD34⁺), which showed anti‐inflammatory properties. Signs of elevated anxiety, depressive‐like behaviour, cognitive deficits and abnormal social behaviour were less marked in FUS‐tg–treated animals. Applied treatments have normalized protein expression of interleukin‐1β (IL‐1β) in the prefrontal cortex and the hippocampus, and of Iba‐1 and GSK‐3β in the hippocampus. Thus, the pre‐symptomatic FUS[1‐359]‐tg mice demonstrate FTLD‐like abnormalities that are attenuated by standard and new ALS treatments, including Neuro‐Cell preparation.