NEWS AND V IEWS

NATURE CELL BIOLOGY VOLUME 9 | NUMBER 2 | FEBRUARY 2007 133

Tau is actin up in Alzheimer’s diseaseGianluca Gallo

The microtubule associated protein tau is involved in the neuropathology of Alzheimer’s disease, however, the mechanistic basis for the involvement of tau is unclear. New evidence indicates that tau may mediate neurotoxicity by altering the organization and dynamics of the actin cytoskeleton.

Alzheimer’s patients present with a slow age-related neurodegeneration involving synaptic loss, axon and dendrite retraction, and the death of neurons. Previous work has identified the microtubule associated protein tau and β-amyloid (Αβ) peptides as potential media-tors of Alzheimer’s development1. However, it is unclear how they participate in the neu-rodegeneration process. On page 139 of this issue, Fulga et al.2 provide evidence that tau induces changes in the organization and stabil-ity of neuronal actin filaments, which in turn contribute to Alzheimer’s-like neurodegenera-tion in Drosophila and mouse model systems for the disease. Furthermore, the authors provide data indicating that Αβ enhances the neurotoxicity induced by tau-mediated actin filament formation. These observations join a growing body of evidence indicating that alter-ations in the actin cytoskeleton may underlie the neuropathology of Alzheimer’s disease and related fronto-temporal dementias in humans, and provide intriguing links between the actin cytoskeleton, tau and Αβ.

The neuropathology of Alzheimer’s disease is classically characterized by the formation of extracellular plaques containing Αβ and intra-neuronal neurofibrillary tangles com-posed of tau1. An additional hallmark of the neuropathology is the presence of structures termed Hirano bodies3. Hirano bodies contain actin filaments, two related actin-associated proteins (the actin depolymerization factor (ADF) and cofilin) and tau4,5. Recent studies suggest that intra-neuronal Hirano body-like

structures (HBLS) may have a causative role in Alzheimer’s disease6,7, but the mechanisms underlying the formation of Hirano bodies are not fully understood.

HBLS formation can be induced in neu-rons by various means, including the direct modulation of the activity of ADF or cofilin6,7 or the activation of Aβ signaling7. Expression of constitutively active forms of ADF or cofi-lin results in HBLS formation6. The ability of these factors to promote the dynamic turnover of actin filaments is regulated by LIM kinase, which turns them off, whereas dephosphoryla-tion by phosphatases (for example, slingshot) turns them on. LIM kinase is, in turn, acti-vated by the p21-activated kinase (PAK) and a decrease in PAK activity is expected to result in an increase in ADF activity. Interestingly, the brains of Alzheimer’s patients exhibit decreased levels of PAK protein and activity, and neurons deficient in PAK activity exhibit HBLS contain-ing ADF and cofilin8. These observations sup-port a role for active actin depolymerization factors in generating HBLS6,7. Fulga et al. dem-onstrate that tau is not merely a component of HBLS, but is also involved in their formation2. The authors show that in both Drosophila and mice, tau leads to the accumulation of F-actin filaments in HBLS-like structures. These struc-tures, which contain tau, F-actin, ADF and cofilin, resemble Hirano bodies observed in the brains of patients suffering from the dis-ease. In addition, they find that tau is able to crosslink actin filaments in vitro, thus provid-ing mechanistic insights into the role of tau in F-actin filaments accumulation.

The cell biological mechanisms underlying neurodegeneration in Alzheimer’s disease have yet to be fully elucidated. However, one aspect

of neuronal cell biology, axonal transport (involving the transport of newly synthesized proteins to axon tips and of signalling mol-ecules from distant synapses to the nucleus in a microtubule-dependent manner), may be of specific relevance. Given its importance, impairments in axonal transport will negatively affect the health of neurons and deficits in axonal transport are observed in animal model systems of Alzheimer’s before other pathologi-cal hallmarks9. The formation of HBLS in neu-rons results in decreased microtubule content in neuronal processes, distal to the location of the HBLS, and may therefore impair axonal transport6. HBLS also stalls the transport of amyolid precursor protein (APP)-containing vesicles7. Thus, HBLS may be responsible for the axonal transport deficits observed before the onset of Alzheimer’s neuropathology and neuronal death. However, the role of HBLS in disrupting axonal transport in pre-pathological models of Alzheimer’s has yet to be clarified.

The development of Alzheimer’s pathology may involve a vicious feed-forward mechanism driven by stalling the axonal transport of APP that, in turn, results in additional Aβ produc-tion and deposition7. Although the first step in the sequence of events is unknown, it seems likely that a blockade of transport at discrete locations along neuronal processes would result in increased accumulation of Aβ in the brain due to blockade of the axonal transport of APP. This accumulation of APP and/or Aβ may then act in a feed-forward manner to fur-ther stall axonal transport. The observation by Fulga et al. that Aβ increases the formation of tau-mediated HBLS2 may be a crucial aspect of the proposed feed-forward mechanism result-ing in Alzheimer’s pathology. In addition, tau

Gianluca Gallo is in the Drexel University College of Medicine, Department of Neurobiology and Anatomy, 2900 Queen Lane, Philadelphia, PA 19129, USA.e-mail: Gianluca.Gallo@DrexelMed.edu

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134 NATURE CELL BIOLOGY VOLUME 9 | NUMBER 2 | FEBRUARY 2007

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also undergoes axonal transport and may accu-mulate intracellularly due to transport deficits, which could then further promote HBLS.

In the context of this feed-forward model, it is interesting to consider data comparing the effects of low and high doses of Aβ on the neuronal cytoskeleton. Sub-lethal doses of Aβ induce HBLS in neurons and increase ADF and cofilin activity7, whereas lethal doses of Aβ decrease ADF and cofilin activ-ity through activation of LIM kinase, and do not induce HBLS10. However, in the lat-ter case, actin filament content is increased throughout neuronal processes contacting extracellular Aβ10. Moreover, a study detect-ing that deficits in PAK signalling could lead to HBLS formation used human brains from patients with ‘moderate’ Alzheimer’s disease. Conversely, a study which detected increased LIM kinase activity focused on regions of human brains with strong neurodegenera-tive phenotypes likely to reflect later stages of pathology. Collectively these observa-tions suggest a speculative revision of the feed-forward model for the progression of HBLS-driven neurodegeneration (Fig. 1). As Aβ begins accumulating in the Alzheimer’s brain, it may drive HBLS formation through

activation of ADF and cofilin6,7,8(Fig. 1a, b). At later stages, as Aβ content increases (Fig. 1c–e), it may activate mechanisms that con-tribute further to axonal and dendritic degen-eration or retraction by promoting actin filament polymerization, and perhaps filament stabilization through increased LIM kinase activity in neuronal processes10. Decreases in actin-filament turnover or increases in axonal actin-filament content lead to axon retraction through myosin II-dependent contractil-ity11,12,13, which may occur during later stages of pathology. It will be interesting to further determine the function of tau in regulating axonal actin filaments, and in particular, to examine whether tau phosphorylation is involved in promoting HBLS formation, as suggested by Fulga et al.2

Numerous questions are raised by the accu-mulating evidence that actin filaments, ADF and/or cofilin and its regulatory kinase path-ways, tau and Aβ may function in concert to give rise to aspects of Alzheimer’s disease pathology: could tau regulate ADF and/or cofilin activity and, if so, how? How does Aβ increase the pro-pensity of tau to induce HBLS? What are the relevant phosphorylation sites on tau, and the kinases that regulate them? Importantly, could

HBLS also block the transport of tau and lead to local tau accumulations?

In conclusion, actin filament-based struc-tures are being identified as important play-ers in the complex pathology of Alzheimer’s disease and related dementias. Although much remains to be learned, the study by Fulga et al.2 demonstrates novel interactions between the classic ‘bad guys’ in Alzheimer’s disease, tau and Aβ, and the formation of actin-containing HBLS.

1. Godert, M. & Spillantini, G. Science 314, 777–781 (2006).

2. Fulga, T. et al. Nature Cell Biol. 9, 139–148 (2007).3. Mott, R. T. & Hulette, C. M. Neuroimaging Clin. N. Am.

15, 755–765 (2005).4. Maciver, S. K. & Harrington, C. R. Neuroreport 23,

1985–1988 (1995).5. Galloway, P. G., Perry, G., Kosik, K. S. & Gambetti, P.

Brain Res. 403, 337–340 (1987).6. Minamide, L. S., Striegl, A. M., Boyle, J. A., Meberg,

P. J. & Bamburg, J. R. Nature Cell. Biol. 2, 628–636 (2000).

7. Maloney, M. T., Minamide, L. S., Kinley, A. W., Boyle, J. A. & Bamburg, J. R. J. Neurosci. 25, 11313–11321 (2005).

8. Zhao, L. et al. Nature Neurosci. 9, 234–242 (2006).9. Stokin, G. B. et al. Science 307, 1282–1288 (2005).10. Heredia, L. et al. J. Neurosci. 26, 6533–6542 (2006).11. Gallo, G., Yee, H. F. Jr. & Letourneau, P. C. J. Cell. Biol.

158, 1219–1228 (2002).12. Aizawa, H. et al. Nature Neurosci. 4, 367–373

(2001).13. Gallo, G. J. Cell Sci. 119, 3413–3423 (2006).

Time

Synapses

Axo

n

APP vesicle Aβ HBLS Actin filaments

a b c d e

Low level ofAβ accumulation

HBLS inhibittransport of APP

vesicle

Higher levelsof Aβ activate

LIM kinase

Refraction ofdistal process

and lossof synapses

Inactive ADF/cofilin

Increases inactin filament

content

ADF/cofilinactivation Increased Aβ

production

Possible blockof tau transport

and accumulationof tau

HBLSformation

Tau may promoteHBLS formation

Figure 1 Schematic representation of a model for HBLS-mediated development during Alzheimer’s disease pathology. (a) In a healthy situation, APP transport along the axon occurs normally (red arrows) and there is a low extracellular accumulation of Aβ. As levels of Aβ signalling increase during early pathology, they initiate the formation of HBLS through ADF and/or cofilin activation. (b) Tau promotes HBLS formation. Aβ may potentiate the effects of tau on HBLS

formation by signalling directly to tau, or possibly by regulating ADF and/or cofilin in concert with Aβ-independent alterations in tau function. (c) HBLS block axonal transport and lead to accumulation of APP-containing vesicles, and perhaps also of tau protein. (d, e) As Aβ levels increase intracellularly at sites of stalled transport, ADF and/or cofilin is inactivated, giving rise to increased levels of actin filaments (d), resulting in synapse loss and process retraction (e).

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