Amyloid-β may be released from non-junctional varicosities of axons generated from abnormal tau-containing brainstem nuclei in sporadic Alzheimer’s disease: a hypothesis

Abstract

How can the relatively abruptly beginning formation of Aβ deposits be explained? That so little is known about this process is all the more remarkable when one considers that Aβ precipitations develop with such consistency during the course of the AD-associated pathological process that they belong to the hallmark lesions of AD [22, 33, 43]. Ear-lier findings could show that Aβ protein does not enter the extracellular space of the CNS from serum via the vascu-lature, via strongly vascularized ependymal organs, or by way of the choroid plexus, nor is it generated by astrocytes, oligodendrocytes, or microglia cells [ 32]. A β protein aggre-gates are the result of a sequential cleavage of an amyloid precursor protein, which is a physiological constituent of the cellular membranes of nerve cells [22, 33]. Neuronally generated soluble and diffusible Aβ is presumed to equili-brate within the interstitial fluid of the CNS and, from there, it may enter the cerebrospinal fluid that occupies the ventricles and subarachnoid space [3]. At seeds in the interstitial space, soluble oligomeric Aβ may aggregate and form insoluble plaque-like deposits [44].It is unlikely that all types of nerve cells are equally capable of generating Aβ, and, for instance, the nerve cells of the enteric as well as peripheral nervous systems are not known to do so. Nor do all neuronal types within the CNS produce Aβ, inasmuch as Aβ deposition is not ubiquitous there. Rather, Aβ deposition consistently occurs at spe-cific CNS sites according to a distinct developmental and distributional pattern [46, 47]. In general, Aβ deposits are rare in the white substance but they do tend to appear in the gray matter where the somatodendritic compartments of projection neurons are located. Even within the gray matter, regions with high densities of Aβ plaques, e.g., the All cases of sporadic Alzheimer’s disease (AD) are neu-ropathologically characterized by disease-related lesions that develop at specific sites in the human brain and gradu-ally disperse from there into hitherto uninvolved regions [5, 14, 24, 35–37, 44]. Central to this pathological process are abnormal alterations of the neuronal cytoskeleton that consist mainly of hyperphosphorylated and aggregated tau protein [17, 21, 25–27, 30, 31]. Involved nerve cells first can be seen in brainstem nuclei that diffusely project to the cerebral cortex. Among others, these include the noradren-ergic locus coeruleus, the serotonergic upper raphe nuclei, and the cholinergic magnocellular nuclei of the basal fore-brain [8]. Later on, in the pathological process, the intra-neuronal inclusions are accompanied by extracellular plaque-like deposits of a second abnormal protein, amy-loid β (Aβ) [10, 11, 42].In the present context, we are referring only to forms of both proteins that can be assessed by light microscopy, i.e., those which precipitate in aqueous solutions of formalde-hyde and can be detected in human autopsy material using immunoreactions and/or silver stains. Plaque-like deposits of aggregated Aβ are located outside of nerve cells, glial cells, or cells of the vascular wall in the interstitial space of the central nervous system (CNS) [46, 47]. Cerebral amyloid angiopathy is a frequently co-occurring lesion [19, 50].