Neurofibrillary lesions

Lewy bodies, neurofibrillary lesions and Pick bodies are intracellular filamentous inclusions. It is now well established that Lewy bodies are made of the protein a-synuclein and both neurofibrillary lesions and Pick bodies of the microtubule-associated protein tau. Mutations in the a-synuclein gene or an increase in its copy number cause autosomal-dominantly inherited forms of Parkinson s disease and dementia with Lewy bodies. Mutations in the tau gene cause a familial form of frontotemporal dementia. Here we review the evidence implicating a-synuclein and tau in these inherited and a number of sporadic neurodegenerative diseases. Collectively, a-synucleinopathies and tauopathies account for the vast majority of cases of late-onset neurodegenerative disease (Tables 45-1 and 45-2). 

Abundant neuritic plaques and neurofibrillary lesions define Alzheimer s disease. Plaques are extracellular deposits made of the fibrillar P-amyloid peptide. The paired helical filament (PHF) makes up the bulk of the intraneuronal neurofibrillary pathology of Alzheimer s disease, with the straight filament (SF) being a minority species. 

Huang Y, Herman MM, Liu J, et al. 1997. Neurofibrillary lesions in experimental aluminum-induced encephalopathy and Alzheimer s disease share immunoreactivity for amyloid precursor protein, A beta, alpha 1-antichymotrypsin and ubiquitin-protein conjugates. Brain Res 771 213-220. 

In AD neurons, there are three main types of neurofibrillary lesions (NFLs) according to their intracellular localization neurofibrillary tangles (NFTs) inside the cell body and apical dendrites, and neuropil threads (NThs) in distal dendrites and dysrophic neurites, associated with senile plaques. Morphologically, three major subtypes of NFTs can be distinguished, corresponding to different evolutionary stages of these lesions. 

In the same brain region, CKl a is only 2.4-fold increased. In purified tau filaments from AD brains, it comprises up to 0.5% of the preparation by weight (Ghoshal et al., 1999). Kannanayakal et al. (2006) showed that CKla is associated with neurofibrillary lesions, while CK18 is primarily connected with granulovascular degeneration bodies. Taken together, CKl protein is increased in AD tissue, it can phosphorylate tau, and it co-localizes with AD lesions. 

Trojanowski, J.Q. and Lee, V.M. 1995. Phosphorylation of paired helical filament tau in Alzheimer s disease neurofibrillary lesions Focusing on phosphatases. FASEB J. 9 1570-1576... 

The most definitive diagnosis of AD is a postmortem examination of the brain for the presence of two characteristic lesions the neuritic plaque (NP) and the neurofibrillary tangle. Both structures were originally described in 1906 by Alois Alzheimer using silver-based histological stains. The discovery of NPs was hailed as a watershed moment in the history of neurological disease as it helped shift society s perception of age-related dementia from social stigma to physical disease [2]. 

Alzheimer s disease (AD) along with vascular and mixed dementia is the commonest form of dementia affecting older people and accounts for 60-65% of dementia cases, whereas vascular dementia and mixed dementia account for 15-20% of the cases each (1). The Brain of individuals with AD manifest two characteristic lesions senile plaques and intracellular neurofibrillary tangles of the hyperphosphorylated tau protein (2). The amyloid fi-protein (Afi) is the principal component of the senile plaques. It is a peptide of 39-43 amino acids, derived from a larger precursor, the amyloid precursor protein (APP) (Fig. 1). 

Iqbal, K., Alonso Adel, C., El-Akkad, E., Gong, C. X., Haque, N., Khatoon, S., Pei, j. j., Tsujio, L, Wang, J. Z., Grundke-Iqbal, I. (2002). Significance and mechanism of Alzheimer neurofibrillary degeneration and therapeutic targets to inhibit this lesion. J. Mol. Neurosci. 19, 95-99. 

Besides the neuritic plaque, the other diagnostic lesion of AD is the neurofibrillary tangle. Tangles are non-membrane-bound masses of paired helical filaments, usually intermixed with straight filaments, found in the perinuclear cytoplasm of many limbic and cortical neuronal cell bodies. Smaller bundles of these abnormal filaments may occur in many, but not all, of the cortical dystrophic neurites found within and also separate from the neuritic plaques. Tangles are also observed in neurons of the subcortical nuclei (e.g., the cholinergic septal nuclei and nucleus basalis of Meynert) that project widely to limbic and association cortices rich in A/9 deposits. 

Of the 12,000 combined genes and ESTs represented on the array, only 10 changed in expression level by a factor of threefold or more, and all were upregulated. In the cortex, mRNAs for neuronal tyrosine/threonine phosphatase 1 and microtubule-associated tau were significantly enhanced. These proteins are both associated with formation/breakdown of intracellular neurofibrillary tangles, a hallmark lesion of Alzheimer s disease. Hyperphosphorylated tau has been found to be the major protein of these neurofibrillary tangles, possibly because of an imbalance in tau kinase and phosphatase activities in the affected neurons [27]. Hyperphosphorylated tau isolated from brains of patients with Alzheimer s disease has been shown to be efficiently dephosphorylated in vitro by protein phosphatases 1, 2A, and 2B. Additionally, selective inhibition of protein phosphatase 2A by okadaic acid in metabolically competent rat brain slices has been shown to induce a hyperphosphorylation and accumulation of tau like that in Alzheimer s disease [28]. Thus, upregulation of neuronal phosphatase 1 by EGb 761 could play a neuroprotective role in the brain. 

Kang, J., Lemaire, H.G., Unterbeck, A., Salbaum, J.M., Masters, C.L., Grzeschik, K.H., Multhaup, G., Beyreuther, K. and Mtiller-Hill, B. 1987. The precursor of Alzheimer s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325 733-736 Kannanayakal, T.J., Tao, H., Vandre, D.D. and Kuret, J. 2006. Casein kinase-1 isoforms differentially associate with neurofibrillary and granulovacuolar degeneration lesions. Acta Neuropathol. (Berlin) 111 413-421... 

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