Moran Boimel

These results provide a link between tau autoimmunity and tauopathy-like abnormalities and indicate potential dangers of using tau for immunotherapy. This experimental autoimmune tauopathy-like model is due to a pathogenic immune response against an intraneuronal antigen and is not related to myelin antigens.

Statin treatment has been associated with a reduced risk of Alzheimer disease and decreased amyloid deposition in mouse models. No animal studies have reported effects of statins on tau aggregates and neurofibrillary tangles (NFTs), the pathological hallmarks of Alzheimer disease that correlate with dementia. We investigated the effect of statins on NFTs in a transgenic mouse tauopathy model and found the following: 1) 1-month treatment with the blood-brain barrier-permeable agent simvastatin in normocholesterolemic aged mice significantly reduced the NFT burden and decreased lectin-positive microglia; 2) simvastatin significantly decreased NFTs and improved T-maze performance in young animals treated for 8 months; 3) treatment of hypercholesterolemic mice for 5 months with blood-brain barrier-impermeable atorvastatin markedly reduced the NFT burden and decreased lectin-positive microglia; 4) nonstatin cholesterol-lowering strategies showed a modest NFT decrease compared with statin treatment; and 5) there was a positive correlation between microglial and NFT burden (r = 0.8). Together, these results suggest that statins reduce NFT burden irrespective of blood-brain barrier permeability at both early and late ages in long- and short-term treatment paradigms and under normocholesterolemic and hypercholesterolemic conditions. The decrease in microglia, coupled with the limited effect of nonstatin cholesterol lowering, suggests that the anti-NFT effect of statins may be related to their anti-inflammatory and not necessarily to their cholesterol-lowering properties. Statins may provide therapy against NFTs in tauopathies, particularly when NFTs are the major neuropathologic component.

It has now become clear that amyloid immunization, while displaying clearance of amyloid, not only caused neuroinflammation, but did not improve cognitive impairment (and did not reduce the neurofibrillary-tangles (NFTs)). As NFTs are the best correlate with dementia, targeting the NFT pathology seems to be a preferential goal. As an aggregated protein, tau in the NFTs - seems to be a candidate for immunotherapy. Yet, the encephalitogenicity of full-length tau recently reported by us (Arch Neurol, 2006) demands to selectively target pathological tau and address both, efficacy and safety. Here we set up to specifically target pathologically phosphorylated (P)-tau conformers by immunizing NFT-mice with NFT-related P-tau peptides, using an immunization protocol aimed to predispose a proinflammatory milieu in CNS, similarly to what we used when the neurotoxicity of tau protein was detected (i.e., the use of complete-Freund’s-adjuvant (CFA) with pertussis-toxin (PT)). We immunized NFT-mice with a mixture of three tau-peptides phosphorylated at five residues characteristic of NFT-pathology with CFA and PT. Clinical, immunological and pathological evaluations were performed. Anti-P-tau Abs were detected in sera of tau-immunized mice. However, no neurological deficits were noted following P-tau-immunotherapy for at least 8 months. Reduced NFT-burden (∼40%; p < 0.001) was noticed in the brains and spinal cords of immunized animals relative to controls, as indicated by Gallyas-staining and with AT8- and AT180-immunohistochemistry This was accompanied with an increase (∼20%; p = 0.01) in microglial burden as indicated by lectin staining. Our results show: 1. A decreased NFT-burden following P-tau-immunotherapy. This is in accord with Asuni et al. (2007) who used a similar approach of immunizing mice against NFTs, yet with a different P-tau immunogene and immunization protocol (without CFA + PT). 2. Presence of anti-P-tau Abs in the sera of immunized mice with no evidence of clinical deficits, indicating that these specific P-peptide-immunogens used by us are not encephalitogenic, in contrast to the encephalitogenicity of full-length tau, demonstrated by us previously. This anti-NFT effect induced by immunotherapy targeting pathologically phosphorylated tau, together with the lack of encephalitogenicity of these P-peptide-immunogens, points to the therapeutic anti-NFT potential of P-tau-immunotherapy.