Focusing the amyloid cascade hypothesis on N-truncated Abeta peptides as drug targets against Alzheimer’s disease

Abstract

Although N-truncated Aβ variants are known to be the main constituent of amyloid plaques in the brains of patients with Alzheimer’s disease, their potential as targets for pharmacological intervention has only recently been investigated. In the last few years, the Alzheimer field has experienced a paradigm shift with the ever increasing understanding that targeting amyloid plaques has not led to a successful immunotherapy. On the other hand, there can be no doubt that the amyloid cascade hypothesis is central to the etiology of Alzheimer’s disease, raising the question as to why it is apparently failing to translate into the clinic. In this review, we aim to refocus the amyloid hypothesis integrating N-truncated Aβ peptides based on mounting evidence that they may represent better targets than full-length Aβ. In addition to Aβ peptides starting with an Asp at position 1, a variety of different N-truncated Aβ peptides have been identified starting with amino residue Ala-2, pyroglutamylated Glu-3, Phe-4, Arg-5, His-6, Asp-7, Ser-8, Gly-9, Tyr-10 and pyroglutamylated Glu-11. Certain forms of N-truncated species are better correlates for early pathological changes found pre-symptomatically more often than others. There is also evidence that, together with full-length Aβ, they might be physiologically detectable and are naturally secreted by neurons. Others are known to form soluble aggregates, which have neurotoxic properties in transgenic mouse models. It has been clearly demonstrated by several groups that some N-truncated Aβs dominate full-length Aβ in the brains of Alzheimer’s patients. We try to address which of the N-truncated variants may be promising therapeutic targets and which enzymes might be involved in the generation of these peptides

Oleuropein aglycone protects against pyroglutamylated-3 amyloid-ß toxicity: biochemical, epigenetic and functional correlates

“…Besides full-length Aß peptides, a variety of different N-truncated Ab peptides have been identified within the cored and diffuse amyloid plaques in the AD brain starting with amino residue Ala-2, pyroglutamylated Glu-3, Phe-4, Arg-5, His-6, Asp-7, Ser-8, Gly-9, Tyr-10, and pyroglutamylated Glu-11 (Antonios et al, 2013;Bayer and Wirths, 2014;Lemere et al, 1996;Saido et al, 1995).…”

A Greek Tragedy: The Growing Complexity of Alzheimer Amyloid Precursor Protein Proteolysis

“…Indeed, a series of studies on human CSF has identified numerous APP N-terminal fragments (29) and N-terminally extended A␤ species that may have (patho)physiological functions (44,45). Evidence also exists for the N-terminal truncation of the A␤ peptide at every one of its first 11 amino acids, although again, the biological relevance of the majority of these species remains uncertain (46). At least one N-terminally truncated species of A␤ (A␤5-X) has been shown to increase in the CSF of patients treated with a BACE1 inhibitor, suggesting that it is liberated in a BACE1-independent manner and that the protease responsible for its liberation acts in direct competition with BACE1 (47).…”

CuII Binding to Various Forms of Amyloid‐β Peptides: Are They Friends or Foes?

“…Nevertheless, according to the amyloid cascade hypothesis first proposed in the 1990s, [6] the imbalance between production and clearance of the A peptides is the origin of the accumulation of peptides that further leads to the aggregation of the soluble monomeric peptide into fibrils and amorphous aggregates detected in the senile plaque. [3][4][5][6][7][8][9] The amyloid cascade is an early event and plays a causal role in AD (Scheme 1). The complete aggregation pathway from the monomeric peptide to the fibrils contains several steps including oligomers, protofibrils, and fi-etiology of the disease.…”

“…[9,[24][25][26] The reason for such heterogeneity is unclear. In seminal reports by Masters and co-workers, [27,28] the quantity of A 4-n was found to be predominant in the amyloid deposits of AD patients.…”