Neurofibrillary Tangles and the Deposition of a Beta Amyloid Peptide with a Novel N-Terminal Epitope in the Brains of Wild Tsushima Leopard Cats

James K Chambers,Kazuyuki Uchida,Hajime Tsujimoto,Hiroyuki Nakayama,Tomoyuki Harada,Masaya Tsuboi,Noriaki Miyoshi,Masahito Kubo,Masumi Sato,Hiroaki Kawaguchi,Chad A Dickey

doi:10.1371/journal.pone.0046452

Abstract

Beta amyloid (Aβ) deposits are seen in aged individuals in many of the mammalian species that possess the same Aβ amino acid sequence as humans. Conversely, neurofibrillary tangles (NFT), the other hallmark lesion of Alzheimer’s disease (AD), are extremely rare in these animals. We detected Aβ deposits in the brains of Tsushima leopard cats (Prionailurus bengalensis euptilurus) that live exclusively on Tsushima Island, Japan. Aβ42 was deposited in a granular pattern in the neuropil of the pyramidal cell layer, but did not form argyrophilic senile plaques. These Aβ deposits were not immunolabeled with antibodies to the N-terminal of human Aβ. Sequence analysis of the amyloid precursor protein revealed an amino acid substitution at the 7th residue of the Aβ peptide. In a comparison with other mammalian animals that do develop argyrophilic senile plaques, we concluded that the alternative Aβ amino acid sequence displayed by leopard cats is likely to be related to its distinctive deposition pattern. Interestingly, most of the animals with these Aβ deposits also developed NFTs. The distributions of hyperphosphorylated tau-positive cells and the two major isoforms of aggregated tau proteins were quite similar to those seen in Alzheimer’s disease. In addition, the unphosphorylated form of GSK-3β colocalized with hyperphosphorylated tau within the affected neurons. In conclusion, this animal species develops AD-type NFTs without argyrophilic senile plaques.

Highlights

Neurofibrillary tangles (NFT), one of the diagnostic lesions of Alzheimer’s disease (AD), are rarely found in non-human animal brains
The hyperphosphorylated tau-positive cells first appeared in the parahippocampal gyrus, and they subsequently spread through regions CA1 to CA3 of the hippocampus and into the ectosylvian gyrus in the more severely affected cases (Figure 1A)
Ab42 was deposited in a speckled pattern (Figure 1B); these deposits were very diffuse, and none of these cases were stained with periodic acid-methenamine silver (PAM) staining

Summary

Introduction

Neurofibrillary tangles (NFT), one of the diagnostic lesions of Alzheimer’s disease (AD), are rarely found in non-human animal brains. The etiology of AD is yet to be elucidated, the ‘‘amyloid hypothesis’’ is widely accepted to explain its pathogenesis [1] According to this hypothesis, the age-dependent accumulation of beta amyloid (Ab) peptides in the brain induces a subsequent cascade that culminates in NFT formation. The AD-related alterations that occur in the brains of animals such as monkeys and dogs have been well studied [2], [3], [4], [5], [6] These animals frequently form senile plaques with aging, they rarely develop NFT [7], [8], [9]. Even in the few reported animal cases of NFT, no pathological examinations were performed to exclude other diseases that could have caused the NFT to develop [10], [11]. It has been a major interest whether AD is a humanspecific disease [12], [13]

Methods

Results

Conclusion