Neurofibrillary Tangles of Aβx-40 in Alzheimer’s Disease Brains

Abstract

Abstract. The two pathognomonic lesions in the brain of AD patients are senile plaques and intraneuronal neurofibrillary tangles (NFT). Previous studies have demonstrated that amyloid-␤ (A␤) is a component of both senile plaques and NFTs, and have showed that intracellular accumulation of A␤ is toxic for cells and precedes the appearance of extracellular amyloid deposits. Here we report that there are numerous intraneuronal NFT and extraneuronal NFT immunoreactive for A␤ x-40 in which there is no co-localization with tau staining suggesting the existence of two different neurodegenerating populations associated with the intracellular accumulation of either tau protein or A␤ x-40 in AD.Keywords: Amyloid-␤, A␤ peptides, immunohistochemistry, neurodegeneration, phosphorylated-tau, tau protein Alzheimer's disease (AD) is a neurodegenerative disease characterized by the progressive and irreversible destruction of neurons in the cerebral cortex. There are two pathognomonic lesions in the brain of AD patients: senile plaques, composed mainly of extracellular aggregates of amyloid-␤ peptides (A␤) [1], and intraneuronal neurofibrillary tangles (NFT), consisting of paired helical filaments (PHF) [2] composed primarily of hyperphosphorylated tau protein [3,4]. The relationship between these processes is uncertain and still not completely understood. The existence of intraneuronal A␤ has been known for many years. Masters and collaborators published in 1985 that A␤, initially termed amyloid A4, is deposited first intraneuronally as NFT and subsequently in the extracellular space, associated with senile plaques and blood vessels [5]. Later on, the immunolabeling of most intraneuronal NFT (iNFT) and extraneuronal NFT (eNFT) with anti-A␤ antibodies was replicated in several laboratories [6][7][8] However, other studies failed to find A␤ immunolabeling associated with iNFT [9][10][11] or with both iNFT and eNFT [12].Later on, immunostaining with specific antibodies against the C-terminal fragment of either A␤ 40 or A␤ 42 (A␤ x-40 or A␤ x-42 , respectively) enabled the visualization of A␤ 42 associated with iNFT where it was seen to collocalize with tau, whereas A␤ 40 did not associate at all or to a far lesser degree [13][14][15]. Additionally, it was reported that numerous eNFT appeared stained for A␤ x-40 , which was interpreted as a secondary deposition over remnants of iNFT exposed in brain tissue once the cells died; however, evidence of colocalization of A␤ x-40 with tau protein in these eNFT was lacking [16].Studies in cell cultures have shown that both A␤ 42 and A␤ 40 can be intracellularly produced in neurons (but apparently not in other types of cells) [17,18], mainly in the trans-Golgi network, although production of A␤ 42 is observed as well in the endoplasmic reticulum [19]. Numerous studies have shown that the intraneuronal accumulation of A␤ may be toxic and precedes its extracellular deposition both in AD brains and in transgenic mice models of the disease

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

“…More and more evidence demonstrates that iAβ is responsible for early synaptic dysfunction and neuronal loss, plaque formation and cognitive impairment; in other words, iAβ is the toxic Aβ species [128]. It was demonstrated by immunochemistry that iAβ is able to form NFTs [132]. Accumulation of iAβ precedes tau hyperphosphorylation and is associated with microtubular degeneration.…”

Safety, tolerability and immunogenicity of an active anti-Aβ40 vaccine (ABvac40) in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase I trial

“…In addition, Aβ 40 is the main component of amyloid deposition occurring in cerebral amyloid angiopathy (CAA) [ 14 ], which has a prevalence of about 80–90% in patients with AD [ 15 ]. In keeping with this, previous studies have demonstrated that specific anti-Aβ 40 antibodies label intra- and extra-neuronal NFTs in the entorhinal cortex and the hippocampus of AD brains, and that these do not co-localise with tau NFTs, suggesting the presence of degenerating neuronal populations filled with C-terminal fragments of Aβ x-40 [ 16 ].…”

“…Although Aβ 42 is regarded as the most toxic species, other studies have shown that Aβ 40 can also form cytotoxic aggregates [ 9 , 53 , 54 ]. Additionally, it has been observed that the levels of insoluble Aβ 40 in the brain of patients with AD increase substantially in association with the onset of dementia [ 11 , 12 ], and we have found large numbers of degenerating neurons filled with C-terminal fragments of Aβ x-40 (but not Aβ x-42 ) in the entorhinal cortex of AD brains [ 16 ]. These results support the idea that Aβ 40 could play a relevant role in the pathophysiology of AD.…”

The PERK-Dependent Molecular Mechanisms as a Novel Therapeutic Target for Neurodegenerative Diseases

“…The above-mentioned pathological aggregates constitute the primary biomarkers for AD diagnosis [24]. Senile plaques are mainly composed of the pathological form of Aβ, whereas the major component of NFTs is the hyperphosphorylated form of tau protein [25,26]. Numerous hypotheses regarding the AD etiology have been presented, but the AD pathogenesis still remains not fully understood [27].…”