Soluble Aβ oligomer production and toxicity

Abstract

For nearly 100 years following the first description of this neurological disorder by Dr. Alois Alzheimer, amyloid plaques and neurofibrillary tangles have been hypothesized to cause neuronal loss. With evidence that the extent of insoluble, deposited amyloid poorly correlated with cognitive impairment, research efforts focused on soluble forms of Aβ, also referred as Aβ oligomers. Following a decade of studies, soluble oligomeric forms of Aβ are now believed to induce the deleterious cascade(s) involved in the pathophysiology of Alzheimer’s disease. In this review, we will discuss our current understanding about endogenous oligomeric Aβ production, their relative toxicity in vivo and in vitro, and explore the potential future directions needed for the field.

Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

“…Each fraction was subjected to a panel of commercially available antibodies detecting human αSyn (LB509, 4B12), mouse/human αSyn (4D6), phosphorylated and misfolded αSyn (pS129-αSyn and Syn514), and to a panel of antibodies generated to detect oligomeric and aggregated amyloid proteins (A11, OC, Officer), including o-αSyn (Syn33, F8H7) (23). We also included analyses with the 6E10 antibody detecting Aβ [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] to determine whether the putative o-αSyn might be coupled to Aβ as a hybrid oligomer (24). Although a clear signal was detected in fraction 38, likely because of soluble APP or Aβ protofibrils, the pattern obtained with 6E10 was distinct from those found with αSyn antibodies.…”

“…α-synuclein | oligomer | memory | Alzheimer's disease | synapsins A lthough abnormal protein aggregates in the form of amyloid plaques, neurofibrillary tangles, and Lewy bodies (LB) characterize neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease, an accumulating body of evidence indicates that soluble multimeric species of these proteins, also known as oligomers, might underlie the deleterious cascades of molecular changes ultimately resulting in these chronic brain disorders (1)(2)(3). In this context, we define soluble endogenous amyloid oligomers as multimeric assemblies that (i) remain soluble in aqueous buffers following ultracentrifugation, (ii) are SDS-resistant following tissue lysis, (iii) are separated in liquid-phase chromatography, and (iv) are immunoreactive to at least two different antibodies for that amyloid molecule.…”

Neurotransmitter receptor and time dependence of the synaptic plasticity disrupting actions of Alzheimer's disease Aβ in vivo

“…Although the neuropathological hallmark plaques are composed largely of fibrillar Ab, most attention has been devoted to investigating the pathophysiological role of non-fibrillar, water-soluble forms of Ab [5,6]. Considerable progress has been achieved in elucidating the disruptive actions of soluble Ab on synaptic transmission and plasticity of that transmission [7][8][9].…”

Levels of Soluble Apolipoprotein E/Amyloid-β (Aβ) Complex Are Reduced and Oligomeric Aβ Increased with APOE4 and Alzheimer Disease in a Transgenic Mouse Model and Human Samples*

“…However, soluble A␤ and oA␤ do correlate with cognitive decline and disease severity in humans (14). oA␤ is also detected in FAD-Tg mice and is associated with memory decline (14).…”