NFT-Specific Tau Vaccine Arrests Tangle Progress

One key limitation to this study is that no cognitive or motor function data are presented. In prior studies, however, preventive and therapeutic vaccination in similar murine models of tau neuropathy has led to relative improvements in such functions, proportional to the reduction in neuropathology.

Another limitation is of interpretation of the results, and possibly of the actual effects of the vaccine therapy itself. The authors note that the burden of NFT in treated animals from Group III — aged 22 mo at autopsy, but whose immunization was delayed until 18 mo of age (ie, a full year after the onset of neuropathology) — was similar to that in untreated mice shortly before (Group I) or shortly after (Group II) that onset at autopsy. Because autopsied Group II animals were of similar age to the the age at which vaccination was initiated in Group III, and unvaccinated Group II animals’ neuropathology burden was similar to that present months after treatment in animals that were initially treated at a similar age, the authors suggest that the apparently similar NFT burdens after several months of vaccination in the latter group suggest that the treatment had arrested the further accumulation of tau pathology following vaccination, rather than having actively cleared it. However, as they also note, it is also possible that their tau vaccine did remove existing tau inclusions, but that the rate of active clearance of tau pathology was equal to the rate of new NFT accumulation.(1) This is quite plausible, granted the very rapid progression of tau pathology in these animals when left untreated, and even more so granted their relatively brief period of treatment: Group III was sufficiently far into their shortened life expectancy as to necessitate abbreviated (6 mo) therapy, relative to the 9-10 mo afforded to Groups I and II. Thus, a longer period of antibody-mediated clearance might have afforded a more thorough therapeutic effect.

At a minimum, even a vaccine that only arrested the burden of tau pathology could contribute to the prevention of significant age-related cognitive decline if administered in middle age. And in aging humans, the development of neurofibrillary tangles occurs over the course of decades, rather than months as in these animals; thus, even a moderate rate of true clearance could in principle be sufficient to lead to a net reduction in NFT burden in humans, and thus to the reversal of one component of brain aging.

In either case, several strategies could be explored to enhance the efficacy of such a vaccine. The most obvious is the administration of a series of booster shots, to increase therapeutic antibody titers or to restore putatively flagging numbers in the months (or in humans, perhaps years) after initial vaccination. Note that the investigators only collected a single data point on antibodies targeting pathological tau, taken relatively soon (4 mo) after a single vaccination at a single antigen dose, following which the same, single round of vaccination was left to work for a further 6 (Groups 1 and II) or 2 (Group III)  months in younger and older animals, respectively; this clearly leaves open the potential that a series of rounds of treatment could have been more effective.

Another potential way to enhance the efficacy of a similar vaccine in humans would be to fortify the lysosome with novel hydrolytic enzymes, to enhance its capacity to clear out aggregates which might be targeted to the lysosome by anti-phospho-tau antibodies. While the involvement of lysosomal degradation of aberrant tau species in the therapeutic effects of immunotherapy was not evaluated in this study,(1) such an effect is consistent with the clearance of intraneuronal phospho-tau in these vaccination studies, and with much other data. Vaccination of a Parkinson’s disease transgenic mouse model with α-synuclein, similarly, leads to a reduction of intracellular α-synuclein aggregates;(11) several studies have found that immunotherapy targeting β-amyloid leads to a reduction in intraneuronal forms of the aggregate, and work in Gunnar Gouras’ laboratory, reviewed in an earlier post, finds that antibodies against Aβ can be internalized in AD neuronal culture models of Aβ accumulation and clear intraneuronal Aβ aggregates via the endosomal–lysosomal pathway. Additionally, the authors of the current study(1) also note that immunized K257T/P301S tauopathy mice exhibit changes in cathepsin levels, consistent with lysosomal degradation of pathological tau;(6) in this context, it is notable that the lysosomal-enhancing drug PADK (see a previous post) removes PHF-1 from hippocampal slices, in association with a normalization of impaired synaptic integrity.(10,11) I will note that the authors of the current study(1) do argue against such a mechanism, on the basis that “total tau levels remained unchanged upon immunization of JNPL3 mice [(5) below], and staining with total tau antibodies was comparable in immunized and control pR5 mice (this study), arguing against overtly increased degradation of tau” — but of course, this does not argue against specific degradation of pathological tau species targeted by immunotherapy in their study.(1)

An additional possibility is that the clearance of other intraneuronal aggregates from aging neurons may itself facilitate the additional proteolytic or lysosomal removal of phospho-tau species. The relationship between the accumulation and neurotoxicity of Aβ and aberrant tau is complex,(13) but reducing one will almost certainly reduce the deleterious effects of the other; and, in particular, immunization against Aβ has been reported to lead to the clearance of early phospho-tau species.(14 (and see (15)) This adds a further argument in favor of a comprehensive approach to brain aging and Alzheimer’s disease,  suggesting synergistic rather than merely additive effects of combining therapies targeting Aβ in addition to malformed tau.

Finally, it is also possible that future vaccines might be more specifically targeted to especially pathologically important tau species, or be designed to elicit antibodies with higher avidity for their target. All of these avenues deserve exploration in future studies of this promising therapeutic approach.