Targeting intracellular Aβ42 for Alzheimer's disease drug discovery

Abstract

For years, extracellular deposition of the ''pathologic'' b-amyloid 1-42 (Ab42) in the brain has been considered as the major cause of the appearance of neuritic plaques that are subsequently responsible for neuronal death in Alzheimer's disease (AD). However, recent work has shown that significant amounts of b-amyloid, especially Ab42, are being sequestered within the perikaryon of affected pyramidal neurons prior to the appearance of plaques. This has led us to challenge the prevailing theory and suggest that at least some of the amyloid plaques, specifically the dense-core plaques in the cerebrum and hippocampus, may derive from the lysis of those neurons that are overburdened with intracellular Ab42. We discuss the possible role of intracellular Ab42 accumulation in the development of AD pathology and review an alternate hypothesis, where Ab42 is first accumulated inside the neurons and later released out to the brain parenchyma via neuronal lysis finally forming a dense-core plaque (''InsideOut'' hypothesis). We describe a mechanism for Ab42 internalization into neurons that involves the high affinity interaction between Ab42 and the alpha7 nicotinic acetylcholine receptor (a7nAChR) and the internalization and intracellular accumulation of the Ab42/a7nAChR complex. This alternative hypothesis can account for many of the well-known features of AD pathology, including specific cholinergic and cholinoceptive neuronal and synaptic loss that affects cognitive and memory functions, the distribution, morphology and composition of dense-core plaques, and their association with inflammation. More importantly, it provides the scientific rationale for targeting the mechanisms that lead to the intraneuronal Ab42 as a novel strategy for AD drug discovery. Drug Dev.

Targeting the Alpha 7 Nicotinic Acetylcholine Receptor to Reduce Amyloid Accumulation in Alzheimers Disease Pyramidal Neurons

“…For example, the high-affinity interaction between Aβ42 and α7nAChR provides straightforward explanations for (1) why neurons appear to selectively accumulate Aβ42, rather than the more abundant Aβ40 species, in AD brains, (2) the predominance of Aβ42 as the principal Aβ species found in APs and (3) the selective vulnerability of cholinergic and cholinoceptive neurons to AD pathogenesis. In view of this, α7nAChR could be an important therapeutic target for treatment of AD [77]. In addition, the studies described above further emphasizes the merits of therapeutic strategies aimed at reducing levels of Aβ42 in the blood and cerebrospinal fluids, blocking the initial interaction of Aβ42 and the α7nAChR and maintaining BBB integrity.…”

“…Brain tissue is especially vulnerable to free radical-mediated injury because it utilizes high amounts of oxygen and the brain vasculature is often compromised by atherosclerosis. Recently, more attention has been given to the possibility that free radical injury is a fundamental contributor to neurologic disorders such as acute ischemic stroke, amyotrophic lateral sclerosis, Parkinson's disease, and AD [75][76][77]. Additional studies will be needed to determine the exact nature of the link between aging, oxidative stress, Aβ42 and neuron demise in AD brains.…”

The microglial phagocytic role with specific plaque types in the Alzheimer disease brain

“…Contrary to the popularized dogma that all amyloid plaques arise from extracellular deposition, plaques may originate from vessels [44], neurons [11][12][13][14][15][16][17], Purkinje cell dendritic processes [67] and astrocytes [46]. In one example, recent attention has turned towards pathological events within the neuron suggesting that cell death could come Fig.…”

“…2. Triple immunohistochemical labeling using specific antibodies to A␤42, HLA-DR and GFAP to detect amyloid, microglia and astrocytes, respectively according to previously published methods [16] from inside the cell, leading to lysis of A␤-filled neurons to deposit their contents as dense-core plaques in the brain [11][12][13]15]. In another example, our lab discovered the presence of astrocytic plaques (lysed astrocytes) in the AD brain tissues [46] thereby supporting the existence of distinctive plaque types in the AD brain.…”

“…One such example of microglial-activating material detected in dense-core but not diffuse plaques is a nuclear remnant [11,13,15] as ATP or ADP can induce chemotaxis for cultured microglia through G i/o -coupled P2Y receptors [27], which is completely blocked by either AR-C69931MX, a potent and selective antagonist against P2T AC receptors or pertussis toxin pretreatment [27]. Similarly, neurons make complement components and their message is dramatically induced in AD brain neurons [56].…”