Immunotherapy Targeting Pathological Tau Prevents Cognitive Decline in a New Tangle Mouse Model

Abstract

Harnessing the immune system to clear protein aggregates is emerging as a promising approach to treat various neurodegenerative diseases. In Alzheimer's disease (AD), several clinical trials are ongoing using active and passive immunotherapy targeting the amyloid-␤ (A␤) peptide. Limited emphasis has been put into clearing tau/tangle pathology, another major hallmark of the disease. Recent findings from the first A␤ vaccination trial suggest that this approach has limited effect on tau pathology and that A␤ plaque clearance may not halt or slow the progression of dementia in individuals with mild-to-moderate AD. To assess within a reasonable timeframe whether targeting tau pathology with immunotherapy could prevent cognitive decline, we developed a new model with accelerated tangle development. It was generated by crossing available strains that express all six human tau isoforms and the M146L presenilin mutation. Here, we show that this unique approach completely prevents severe cognitive impairment in three different tests. This remarkable effect correlated well with extensive clearance of abnormal tau within the brain. Overall, our findings indicate that immunotherapy targeting pathological tau is very feasible for tauopathies, and should be assessed in clinical trials in the near future.

Trans-cellular Propagation of Tau Aggregation by Fibrillar Species

“…Although there are potential side effects, such antibodies hold promise as treatments. However, the success of vaccination in mouse models of tauopathy (31)(32)(33)(34)(35) and synucleinopathy (43) has been puzzling in light of the fact that the target proteins are predominantly intracellular. We observed that HJ9.3, a mouse monoclonal antibody against Tau RD, inhibited the trans-cellular propagation of Tau aggregation.…”

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

“…Importantly, as cognitive impairments closely correlate with the extension of tau pathology [132,133], removing neurofibrillary tangles has become one of the main therapeutic goals for the treatment of AD and FTD [134,135]. In this regard, it has been shown that both active and passive immunization against tau reduce its accumulation and slow or prevent behavioral deficits in transgenic mouse models of tauopathy [135][136][137][138][139][140][141][142].…”

Developing Therapeutic Antibodies for Neurodegenerative Disease

“…Similar to the amyloid immunotherapy field, tau active immunization provided the first evidence that pathologic spreading could be reduced in long-term efficacy studies [74][75][76][77]. These studies have more recently been followed by passive immunotherapy studies also showing success in reducing pathology and even rescuing motor deficits in tau transgenic mice [78,79].…”