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Cognitive decline is a common pathological outcome during aging, with an ill‐defined molecular and cellular basis. In recent years, the concept of inflammaging, defined as a low‐grade inflammation increasing with age, has emerged. Infiltrating T cells accumulate in the brain with age and may contribute to the amplification of inflammatory cascades and disruptions to the neurogenic niche observed with age. Recently, a small resident population of regulatory T cells has been identified in the brain, and the capacity of IL2‐mediated expansion of this population to counter neuroinflammatory disease has been demonstrated. Here, we test a brain‐specific IL2 delivery system for the prevention of neurological decline in aging mice. We identify the molecular hallmarks of aging in the brain glial compartments and identify partial restoration of this signature through IL2 treatment. At a behavioral level, brain IL2 delivery prevented the age‐induced defect in spatial learning, without improving the general decline in motor skill or arousal. These results identify immune modulation as a potential path to preserving cognitive function for healthy aging. Synopsis: Delivery of interleukin 2 into the brain via a blood–brain barrier crossing AAV vector prevents cognitive decline in the aging mice. A gene delivery system uses an AAV‐based viral vector coupled with an astrocyte‐specific promoter to drive the expression of the anti‐inflammatory cytokine interleukin 2 in the brain of aged mice.At a molecular level, brain‐specific expression of IL2 in aged mice partially reverted the transcriptional signature of aged glial cells to the baseline state of young glial cells.At a cognitive level, brain‐specific expression of IL2 in aged mice partially restored the spatial learning decline, without improving the general decline in motor skill or arousal. [ABSTRACT FROM AUTHOR]

Background: Single domain antibodies (VHH) are potentially disruptive therapeutics, with important biological value for treatment of several diseases, including neurological disorders. However, VHH have not been widely used in the central nervous system (CNS), largely because of their restricted blood‐brain barrier (BBB) penetration. To overcome this restriction, we designed a gene transfer strategy using BBB‐crossing adeno‐associated virus (AAV)‐based vectors to deliver VHH directly into the CNS. As a proof‐of‐concept, we explored the potential of AAV‐delivered VHH to inhibit BACE1, given its well‐characterized and central role in Alzheimer's disease. Method: In a first step, we generated a panel of novel VHHs targeting BACE1: one of these, VHH‐B9, demonstrates high selectivity for BACE1 and appears to specifically inhibit APP‐cleavage in vitro. On the basis that a substrate‐selective inhibition of BACE1 may overcome the mechanism‐based adverse effects commonly reported in BACE1 inhibitor trials, we selected VHH‐B9 for incorporation into a BBB‐crossing vector. Result: A single systemic dose of AAV‐VHH‐B9 produces positive long‐term (12 months plus) effects on amyloid load, neuroinflammation, synaptic function and cognitive performance, in the AppNL‐G‐F Alzheimer's mouse model, without any overt signs of toxicity. Conclusion: These results suggest that long‐term BACE1 inhibition, with a selective APP‐cleavage inhibitor, may constitute a novel therapeutic approach for Alzheimer's disease. More broadly, we propose that AAV‐mediated VHH delivery will be a useful tool for the treatment of a range of CNS disorders. [ABSTRACT FROM AUTHOR]

Single domain antibodies (VHHs) are potentially disruptive therapeutics, with important biological value for treatment of several diseases, including neurological disorders. However, VHHs have not been widely used in the central nervous system (CNS), largely because of their restricted blood-brain barrier (BBB) penetration. Here, we propose a gene transfer strategy based on BBB-crossing adeno-associated virus (AAV)-based vectors to deliver VHH directly into the CNS. As a proof-of-concept, we explored the potential of AAV-delivered VHH to inhibit BACE1, a well-characterized target in Alzheimer's disease. First, we generated a panel of VHHs targeting BACE1, one of which, VHH-B9, shows high selectivity for BACE1 and efficacy in lowering BACE1 activity in vitro. We further demonstrate that a single systemic dose of AAV-VHH-B9 produces positive long-term (12 months plus) effects on amyloid load, neuroinflammation, synaptic function, and cognitive performance, in the App NL-G-F Alzheimer's mouse model. These results constitute a novel therapeutic approach for neurodegenerative diseases, which is applicable to a range of CNS disease targets., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)