SORLA up-regulation suppresses pathological effects in aged tauopathy mouse brain

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• The Sortilin-related receptor containing LDLR class A repeats (SORLA) is known to reduce amyloid-beta (Aβ) levels.
• Its role in modulating tau pathology in vivo remains largely unexplored.

Purpose of the Study:

• To investigate the in vivo effects of SORLA on tau pathology.
• To determine if SORLA can confer neuroprotection against tau toxicity.

Main Methods:

• Utilized transgenic mouse models (PS19 mice with P301S tau mutation) with either SORLA upregulation (SORLA TG) or SORLA deletion.
• Employed proteomic analysis and single-nucleus RNA sequencing to assess molecular and cellular changes.
• Evaluated pathological markers including tau phosphorylation, seeding, ventricle dilation, synapse loss, long-term potentiation (LTP), and glial activation.

Main Results:

• Transgenic SORLA upregulation attenuated tau phosphorylation, seeding, ventricle dilation, synapse loss, LTP impairment, and glial hyperactivation in aged PS19 mouse brains.
• Proteomic and single-nucleus RNA sequencing revealed suppressed PS19-associated signatures and identified Sema4D-PlexinB1/B2 signaling in glial pathology.
• SORLA deletion exacerbated tau seeding, aggregation, glial hyperactivation, and PlexinB1/B2 induction in PS19 mouse hippocampus.

Conclusions:

• SORLA upregulation confers significant neuroprotection against tau toxicity in the PS19 mouse model.
• SORLA plays a critical role in mitigating tau-induced neurodegenerative processes, including synaptic and glial dysfunction.