Developing therapeutic approaches to tau, selected kinases, and related neuronal protein targets

Abstract

A hallmark of the Alzheimer disease (AD) brain is the presence of inclusions within neurons that are comprised of fibrils formed from the microtubule-stabilizing protein tau. The formation of misfolded multimeric tau species is believed to contribute to the progressive neuron loss and cognitive impairments of AD. Moreover, mutations in tau have been shown to cause a form of frontotemporal lobar degeneration in which tau neuronal inclusions observed in the brain are similar to those seen in AD. Here we review the more compelling strategies that are designed to reduce the contribution of misfolded tau to AD neuropathology, including those directed at correcting a possible loss of tau function resulting from sequestration of cellular tau and to minimizing possible gain-of-function toxicities caused by multimeric tau species. Finally, we discuss the challenges and potential benefits of tau-directed drug discovery programs.

Figure 1.

Schematic of the longest human tau isoform and the other major tau isoforms found in humans that are generated through posttranscriptional splicing of exons 2 (I1), 3 (I2), and 10 (R2). The inclusion or exclusion of exon 10 results in tau with four or three binding repeats within the MT binding domain (4R-tau or 3R-tau), respectively. Amino acid numbers are depicted along the bottom of the longest tau isoform.

Figure 2.

Possible tau-based therapeutic strategies in Alzheimer disease. A loss of tau function might be overcome with microtubule-stabilizing agents or inhibitors of tau hyperphosphorylation and/or acetylation. Potentially toxic tau oligomers or fibrils might be prevented by inhibitors of tau multimeric assembly. Inhibition of HSP90 and the resulting elevation of the chaperones HSP70/HSP40 may increase proteasomal degradation of hyperphosphorylated tau. Misfolded tau multimers might be cleared through enhancement of macroautophagy. Finally, misfolded tau species may be released from cells and internalized by nearby neurons, thereby “seeding” the formation of pathological tau in the recipient cell. If confirmed, this spreading of tau pathology might be inhibited by antibodies that bind misfolded tau in the brain interstitial fluid.

Figure 3.

The assembly of tau into multimers and fibrils. Tau is normally unstructured in solution, and in axons the majority of tau is typically associated with MTs. In AD, tau can become misfolded and assemble into multimeric structures. Certain of these multimers can serve as nucleating structures to which additional tau can be added to yield classical amyloid-type fibrils.