Chronic PD-1 Checkpoint Blockade Does Not Affect Cognition or Promote Tau Clearance in a Tauopathy Mouse Model.

Programmed cell death protein 1 (PD-1) checkpoint blockade with an antibody has been shown to reduce amyloid-β plaques, associated pathologies and cognitive impairment in mouse models. More recently, this approach has shown effectiveness in a tauopathy mouse model to improve cognition and reduce tau lesions. Follow-up studies by other laboratories did not see similar benefits of this type of therapy in other amyloid-β plaque models.

In Vivo Imaging of Tauopathy in Mice.

Alzheimer's disease is characterized by amyloid-β plaques and neurofibrillary tangles composed of tau aggregates. Several β-sheet dyes are already in clinical use to detect amyloid-β plaques by in vivo positron emission tomography (PET), and related dye compounds are being developed for targeting pathological tau aggregates. In contrast to β-sheet binders, antibody-derived ligands should provide greater specificity for detecting tau lesions, and can be tailored to detect various pathological tau epitopes.

Affinity of Tau antibodies for solubilized pathological Tau species but not their immunogen or insoluble Tau aggregates predicts in vivo and ex vivo efficacy.

Background: A few tau immunotherapies are now in clinical trials with several more likely to be initiated in the near future. A priori, it can be anticipated that an antibody which broadly recognizes various pathological tau aggregates with high affinity would have the ideal therapeutic properties. Tau antibodies 4E6 and 6B2, raised against the same epitope region but of varying specificity and affinity, were tested for acutely improving cognition and reducing tau pathology in transgenic tauopathy mice and neuronal cultures.

Sex and Immunogen-Specific Benefits of Immunotherapy Targeting Islet Amyloid Polypeptide in Transgenic and Wild-Type Mice.

Type 2 diabetes mellitus is characterized by the deposition of islet amyloid polypeptide (IAPP) as amyloid in islets, a process thought to be toxic to β-cells. To determine the feasibility of targeting these aggregates therapeutically, we vaccinated transgenic (Tg) mice that overexpress human IAPP and were fed a high-fat diet to promote their diabetic phenotype. Our findings indicate that prophylactic vaccination with IAPP and its derivative IAPP7-19-TT, protects wild-type female mice, but not males, from obesity-induced early mortality, and the derivative showed a strong trend for prolonging the lifespan of Tg females but not males.

Antibody-derived in vivo imaging of tau pathology.

Antibodies or their derivatives as imaging probes for pathological tau protein have great potential, but have not been well studied. In particular, smaller, single-chain-variable antibody fragments (scFv's) are attractive for detecting tau lesions in live subjects. Here, we generated libraries of scFv's and identified numerous phospho-tau-selective scFv's.

Histological staining of amyloid and pre-amyloid peptides and proteins in mouse tissue.

The increased availability of transgenic mouse models for studying human diseases has shifted the focus of many laboratories from in vitro to in vivo assays. Herein, methods are described to allow investigators to obtain well-preserved mouse tissue to be stained with the standard histological dyes for amyloid, Congo Red, and Thioflavin S. These sections can as well be used for immunohistological procedures that allow detection of tissue amyloid and pre-amyloid, such as those composed of the amyloid-β peptide, the tau protein, and the islet amyloid polypeptide.