Selective neuronal degeneration induced by soluble oligomeric amyloid beta‐protein

Abstract

The prevailing amyloid hypothesis for Alzheimer's disease (AD) holds that amyloid beta-protein (Abeta) causes neuronal degeneration by forming neurotoxic fibrillar structures. Yet, many aspects of AD pathology and symptoms are not well explained by this hypothesis. Here, we present evidence that neurotoxicity of soluble oligomeric Abeta closely corresponds to the selective neurodegeneration so distinctly manifest in AD. Selectivity was first observed in vitro, where only the human central nervous system neuronal cells were susceptible to soluble oligomeric Abeta. Furthermore, in mouse cerebral slice treated with soluble oligomeric Abeta, selective regiospecific toxicity was evident in the hippocampal CA1, a division important for memory, but not in the CA3 subfield. The fibrillar Abeta, however, killed neurons in all regions of the cerebral slice cultures and also in cerebellar slices. Remarkably, even at the highest soluble oligomeric Abeta concentrations, cerebellar neurons were completely spared, consistent with one of the hallmark features of AD pathology. Our observation of the selective neurodegeneration of soluble oligomeric Abeta to neurons involved in cognitive function may provide a new opportunity for the development of an effective AD therapy as well as elucidating the pathological mechanism of AD.

Acquisition of conditioned taste aversion is impaired in the amyloid precursor protein/presenilin 1 mouse model of Alzheimer’s disease

“…In more recent years evidence indicates that prior to Aβ deposition increased levels of soluble oligomer forms of Aβ may be toxic to neuronal function and highly correlated with the extent of cognitive dysfunction (Cherny et al, 1999, Lue et al, 1999, Naslund et al, 2000. Electrophysiological studies indicate synthetic or cell-produced forms of soluble Aβ can inhibit long-term potentiation in vitro and in vivo (Lambert et al, 1998, Kim et al, 2003, and in various mouse models of AD, cognitive deficits appear before plaque deposition is evident (Ashe, 2005). Although soluble forms of Aβ were not measured in the current studies, it may be an explanation for the CTA acquisition failure in the young 3-5 month old mice where there was lack of extensive plaque deposition.…”

Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins?

“…Oxidative damage of amyloid-forming proteins increases their propensity to misfold and aggregate in vitro (Rakhit et al 2002 ;Dauer & Przedborski, 2003). Expression of a-synuclein in cells, under oxidizing conditions, promotes cytoplasmic aggregation and cell death (Kim et al 2003 ;Smith et al 2005). Many of the factors listed above are ATP-dependent and would therefore be expected to emerge on aging (Heydari et al 1995 ;Gaczynska et al 2001 ;Soti & Csermely, 2002 ;Ferrington et al 2005 ;Chondrogianni, 2005), when ATP production becomes less efficient.…”

Discovery and characterization of a mammalian amyloid disaggregation activity

“…[3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] Amyloid is toxic when applied exogenously to or when formed within cultured cells. [19][20][21][22][23][24][25][26][27][28][29][30][31][32] Mouse and C. elegans models of amyloid diseases show that the cytotoxicity associated with amyloidogenesis increases with organismal age. 22,33 Postnuclear supernatant (PNS) from C. elegans has recently been shown to disaggregate Ab 1-40 amyloid fibrils, which are linked to Alzheimer's disease.…”