Neurofilaments May Be Essential to Some Tauopathies

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.

Reference:Ishihara T, Higuchi M, Zhang B, Yoshiyama Y, Hong M, Trojanowski JQ, Lee VM. Attenuated neurodegenerative disease phenotype in tau transgenic mouse lacking neurofilaments. J Neurosci. 2001 Aug 15;21(16):6026-35. Abstract

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