The histopathological hallmark of Alzheimer’s disease (AD) is the presence of beta amyloid (Aβ) plaques and neurofibrillary tau (NFT) tangles in the postmortem analysis of brain tissue in a human with a medical history of progressive cognitive decline. Historically, the Amyloid Cascade hypothesis posits that a deposition of Aβ brain tissue triggers a series of pathological events that ultimately gives rise to the clinical symptoms and signs associated with Alzheimer’s disease, such as cognitive impairment and dementia (Karran et al., 2011).

But how can Aβ trigger these events? Dr. Francesca Bartolini from Columbia University studies how microtubules, the molecular skeleton of the cell, undergo post-translational modifications and how these changes can alter microtubule stability. Her lab explores how Aβ can alter microtubule stability, and how this may lead to subsequent collapses in dendritic spines, a common event in AD pathology.

The overarching model of how Aβ affects MT stability considers the role of hyperphosphorylated tau protein, which is a primary component of NFTs. Previous work suggests that Aβ accumulation results in tau hyperphosphorylation, which cannot bind well to MTs. Thus, MTs destabilize, leading to downstream neuronal damage. However, the role of Aβ on MT dynamics in the absence of tau has not been explored; in their recent paper, the Bartolini lab studied this relationship between Aβ and MTs.

In order to explore MT stability, Bartolini’s group leveraged the fact that stabilized MTs are detyrosinated such that a glutamic acid residue is exposed at the C-terminus (referred to as Glu MTs). Tyrosine residues on MTs, on the other hand, are a marker for dynamic MTs. Additionally, NIH3T3 cells were used to isolate the effects on MTs to simply Aβ, as this cell line lacks tau protein entirely. In brief, the Bartolini group found that, in NIH3T3 cells, exposure to neurotoxic levels of Aβ resulted in increased Glu MTs in a RhoA/mDia 1 dependent manner. The RhoA/mDia 1 pathway that leads to stabilization of MTs is as follows: RhoA is a Rho-GTPase that activates the formin mDia1, a protein that has primarily been studied in the context of actin dynamics. It has also been shown to be involved in MT stabilization, but the role of mDia1 on MT dynamics is still largely unclear (Chesarone et al., 2010).

In the figure below, NIH3T3 cells were exposed to soluble Aβ and fixed 2 hours later; immunostaining against detyrosinated Glu MTs revealed that 0.5-1 μM Aβ exposure lead to elevated Glu MTs compared to untreated control, although this level was still less than what was seen in LPA-treated cells (Fig. 1A-B). To identify the underlying mechanism by which these cells manifested their MT stability, the authors also used C3 toxin (a RhoA inhibitor), which resulted in dramatically reduced levels of Glu MTs (Fig. 1C-D). Using siRNA targeting the downstream effector mDia1, the authors also showed that the effect of Aβ on MT stability is lost under conditions of mDia1 knockdown (Fig. 1E-F).

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This is particularly interesting, as it suggests that Aβ may act to stabilize MTs, and that this may in fact contribute to AD neuropathology. This is surprising in that it seems to counter previous studies that suggest that Aβ acts indirectly to destabilize MTs via tau pathology, although the authors of this research suggest that perhaps these two models are not mutually exclusive; they instead suggest that perhaps the MT destabilization that occurs in the presence of tau may be a compensatory mechanism to counteract the overstabilization of MTs by Aβ. They support this model by adding the fact that hyperphosphorylated tau proteins tend to preferentially target stable Glu MTs that are detyrosinated (Yoshiyama et al., 2003; Rapoport et al., 2002). Ultimately, this finding opens a door to studying the role of Aβ on microtubule function; perhaps, tau pathologies can be pinned to the actions of Aβ on MT dynamics.

Pianu, B., Lefort, R., Thuiliere, L., Tabourier, E., and Bartolini, F. (2014). The A 𝛽1-42 peptide regulates microtubule stability independently of tau. J of Cell Sci. 127(5): 1117–1127.

Karran E, Mercken M, De Strooper B.(2011). The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov  10(9):698–712. doi:10.1038/nrd3505

Chesarone, M. A., DuPage, A. G. and Goode, B. L. (2010). Unleashing formins to remodel the actin and microtubule cytoskeletons. Nat. Rev. Mol. Cell Biol. 11, 62-74.

Yoshiyama, Y., Zhang, B., Bruce, J., Trojanowski, J. Q. and Lee, V. M. (2003). Reduction of detyrosinated microtubules and Golgi fragmentation are linked to tau-induced degeneration in astrocytes. J. Neurosci. 23, 10662-10671.

To learn more about the work conducted in Dr. Bartolini’s lab, please attend her talk this Tuesday, April 24th at 4:00pm in the Center for Neural Circuits and Behavior.

Junmi Saikia is a third year MD/PhD student who has developed a dangerous addiction to caffeine whilst pursuing research regarding synaptic plasticity and Alzheimer’s disease.

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