Intraneuronal Aβ42 accumulation in Down syndrome brain

Abstract

Alzheimer's disease (AD) brains display A beta (Abeta) plaques, inflammatory changes and neurofibrillary tangles (NFTs). Converging evidence suggests a neuronal origin of Abeta. We performed a temporal study of intraneuronal Abeta accumulation in Down syndrome (DS) brains. Sections from temporal cortex of 70 DS cases aged 3 to 73 years were examined immunohistochemicallyf or immunoreactivity (IR) for the Abeta N-terminal, the Abeta40 C-terminus and the Abeta42 C-terminus. N-terminal antibodies did not detect intracellular Abeta. Abeta40 antibodies did not detect significant intracellular Abeta, but older cases showed Abeta40 IR in mature plaques. In contrast, Abeta42 antibodies revealed clear-cut intraneuronal IR. All Abeta42 antibodies tested showed strong intraneuronal Abeta42 IR in very young DS patients, especially in theyoungest cases studied (e.g., 3 or 4yr. old), but this IR declined as extracellular Abeta plaques gradually accumulated and matured. No inflammatory changes were associated with intraneuronal Abeta. We also studied the temporal development of gliosis and NFT formation, revealing that in DS temporal cortex, inflammation and NFT follow Abeta deposition. We conclude that Abeta42 accumulates intracellularly prior to extracellular Abeta deposition in Down syndrome, and that subsequent maturation of extracellular Abeta deposits elicits inflammatory responses andprecedes NFTs.

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

“…An exaggeratedly antagonistic vision of the two hallmark lesions in AD (extracellular senile plaques mainly containing A␤ and intraneuronal NFTs composed of hyperphosphorylated tau protein) has crystallized into the idea that A␤ triggers neurodegeneration from the outside of cells and a subsequent tau accumulation damages them from inside. This overly simplistic vision disregards pioneers' results demonstrating that A␤ is a component of both senile plaques and NFTs [5,8,9,32] and also more recent reports showing that intracellular accumulation of A␤ is toxic for cells and precedes the appearance of extracellular amyloid deposits [14,20,[22][23][24][25][26][27]29]. The presence of A␤ x-40 immunoreactivity in the eNFTs as described in the present work, has been known for a long time [13,16], yet contradictory results have also been reported [14,20].…”

“…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 [14,[20][21][22][23][24][25]. Interestingly, intraneuronal accumulation of either A␤ 40 or A␤ 42 has been described in brains of Down syndrome patients aged less than three years [20,26,27]. Furthermore, it has been found that intracellular A␤ deposition precedes the appearance of immunoreactive tau iNFT [20,28] which subsequently were found associated with A␤ 42 in neurites and synapses [15].…”

Molecular Mechanisms of Amyloid Oligomers Toxicity

“…Intraneuronal A␤ accumulation has been identified in AD patients, transgenic mice, and cultured cells [88][89][90][91][92][93][94]. Intraneuronal A␤ accumulation appears prior to extracellular amyloid plaque formation and results in synaptic dysfunction [88,93,[95][96][97][98][99][100][101][102]. A key question that remains to be addressed is whether the intracellular A␤ builds up because a portion of the generated A␤ is not secreted and consequently remains intracellular, or alternatively, whether secreted A␤ is taken back up by the cell to form these intracellular pools [103][104][105][106].…”

Oligomerization of Alzheimer's β-Amyloid within Processes and Synapses of Cultured Neurons and Brain

“…Evidence also indicates that accumulation of A␤42, the first A␤ species found in plaques, occurs intracellularly (Echeverria and Cuello, 2002;Tabira et al, 2002) in AD (Gouras et al, 2000;D'Andrea et al, 2001), Down's syndrome (Gyure et al, 2001;Busciglio et al, 2002;Mori et al, 2002), and transgenic mice that develop A␤ plaques (Wirths et al, 2001;Oddo et al, 2003;Sheng et al, 2003). Additionally, extracellular A␤42 can increase levels of intraneuronal A␤42 (Glabe, 2001).…”