14 Aug 2001

It appears that some tauopathies require the presence of neurofilaments for neurodegeneration to occur. In the 15 August Journal of Neuroscience, Virginia Lee, Takeshi Ishihara, and colleagues at the University of Pennsylvania describe how they were able to reduce dramatically the number of intraneuronal tau aggregates-as well as reduce disease symptoms-in their tau transgenic mice by crossing them with knockout mice lacking particular neurofilament subunits.

Neurofilaments are found in neuropathologic lesions in a number of the tauopathies (e.g., neurofibrillary tangles in Alzheimer's disease; Lewy bodies in Parkinson's disease; axonal spheroids in amyotrophic lateral sclerosis/parkinsonism-dementia complex [ALS/PDC]), but their role in these diseases is unclear. In Alzheimer's, for example, neurofilaments do not appear in tangles until very late in the disease, suggesting that they may have no pathogenic role. On the other hand, neurofilaments are an early and significant component of the tau-containing inclusions found in spinal cord motor neurons in classic ALS, ALS/PDC, and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17).

The Lee group's mouse model recapitulates some of the features of FTDP-17 and ALS/PDC, including tau-containing intraneuronal aggregates in spinal cord motor neurons. Because these inclusions contain neurofilaments, the researchers decided to crossbreed the mice with others that lacked neurofilament subunits L or H (NFL, NFH). Especially in the mice lacking NFL, Lee's group found dramatic reductions in the numbers of tau aggregates in spinal cord and brainstem neurons. The mice deficient in neurofilaments also lived longer, weighed more, and suffered less limb weakness than did the standard tau transgenic mice.

The results suggest that neurofilaments are essential for the formation and pathogenicity of at least some tau aggregates. Interestingly, Lee's group has found that the tau transgenic mice develop neurofilament-negative tau inclusions in the hippocampus and associated areas as they age, similar to the tangles found in normal aging in humans. In this study, the absence of neurofilament did not prevent the formation of hippocampal neuron inclusions, suggesting to the authors that they have identified two separate mechanisms for the formation of tau inclusions, one that is neurofilament-dependent and one that is neurofilament-independent.—Hakon Heimer