The Neural Basis of Alzheimer’s Disease
By: Caitlin Beddows, Posted on: February 26, 2016
Alzheimer’s disease (AD), first described by the physician Alois Alzheimer in 1906, is an insidious progressive neurodegenerative disorder that only can be detected clinically in its final phase. A definitive diagnosis based on antemortem observations is complicated and often misleading (Montine et al., 2012).
A major histopathological criterion of AD, and one that is decisive for its postmortem diagnosis, is the assessment of distinctive alterations within the neuronal cytoskeleton that appear in the form of nonargyrophilic pretangle material (precursor of neurofibrillary lesions that consists of variably soluble aggregates of abnormal tau protein that cannot be degraded by involved nerve cells), argyrophilic neuropil threads (NTs), and neurofibrillary tangles (NFTs) in specific subsets of nerve cells of the human central nervous system (see The Intraneuronal Formation of Abnormal Tau Protein). Accompanying pathological alterations that appear later than the aforementioned intraneuronal changes include extracellular deposits of the pathological protein β-amyloid (see Section The Extracellular Deposition of Abnormal β-Amyloid Protein) and the formation of neuritic plaques (see Section The Appearance and Composition of Neuritic Plaques).
The Neurodegenerative Process
The Intraneuronal Formation of Abnormal Tau Protein
Tau is a special protein that is mainly associated with the cytoskeleton of cells. Microtubules are normally stabilized by the tau protein. In a hyperphosphorylated state, abnormal tau loses its binding capacity to microtubules. A turning point in the degenerative process are pathological alterations of the cytoskeleton, a kind of internal moveable scaffolding occurring in every living cell, which result from the formation of an abnormal and hyperphosphorylated tau protein in a few susceptible types of neurons (Goedert et al., 1997; Goedert, 1999; Mandelkow et al., 2007; Alonso et al., 2008; Iqbal et al., 2009). In healthy nerve cells, the protein tau is one of the several specific cellular proteins that is associated with and stabilizes components of the cytoskeleton. The abnormal but variably soluble and nonargyrophilic pretangle material that initially emerges fills the entire nerve cell (Bancher et al., 1989).
At first, the cell body and the cellular processes of such neurons hardly deviate from their normal shape. In a series of additional steps, this material aggregates to form argyrophilic and nonbiodegradable filaments: the NTs and NFTs that are the hallmarks of AD. NFTs, which often have a flame or cometlike appearance, gradually fill large portions of the nerve cell body and appear black after staining with special silver techniques (Figure 1(a)) (Braak and Braak, 1991a and Braak and Braak, 1991b; Trojanowski et al., 1995; Esiri et al., 1997). Nerve cells that contain NFTs can survive for years despite marked cytoskeletal alterations.
However, they forfeit many of their functional capacities long before premature cell death occurs. After deterioration and disappearance of the host cell, a cluster of the pathological material remains visible in the surrounding brain tissue as a remnant, or the so-called tombstone tangle where it marks the site of the lost neuron (Figure 1(a)). The fact that tombstone tangles are never observed in the absence of fresh pretangle or neurofibrillary lesions accounts for the absence of spontaneous remission in AD patients. In the course of the illness, all of the involved nerve cells proceed through a pretangle phase before developing the argyrophilic filaments. The potential for reversing the pathological process is most probably at its peak during the pretangle phase. Neurofibrillary changes of the Alzheimer type include stable (insoluble) fibrillary inclusions that mainly consist of abnormal and hyperphosphorylated tau protein and develop in a few susceptible types of nerve cells in the central nervous system of the human brain.
The hallmark of AD is precipitation of abnormal proteins at both intraneuronal and extracellular cerebral locations. (a) The final intraneuronal tau deposits represent the neurofibrillary alterations of the Alzheimer type and include three distinct kinds of lesions: Strands of abnormal tau protein located within involved nerve cell bodies (neurofibrillary tangles) and within their dendritic processes (neuropil threads), as well as abnormal fibrous material which accumulates in swollen cellular processes of neuritic plaques. Extracellular ‘tombstone’ tangles mark the sites at which the host nerve cells perished. (b) The plaquelike extracellular deposits are composed chiefly, but not exclusively, of β-amyloid protein. Depending on the texture of the neuropil (i.e., brain tissue consisting of nerve cell and glial cell cellular processes; see Section The Extracellular Deposition of Abnormal β-Amyloid Protein), plaques occur in different sizes and shapes. Most cortical β-amyloid deposits evolve as globular structures with or without a condensed core.
Read more about this in the article Neural Basis of Alzheimer’s Disease, which further discusses the extracellular deposition of abnormal β-Amyloid protein, the appearance and composition of Neuritic Plaques, developmental sequence of the lesional distribution pattern of the intraneuronal cytoskeletal alterations and AD and evolution.
This excerpt was taken from the article Neural Basis of Alzheimer’s Disease by Heiko Braak and Kelly Del Tredici-Braak. The article is included in the PROSE award winning International Encyclopedia of the Social and Behavioral Sciences, Second Edition which offers a source of social and behavioral science reference material that is broader and deeper than any other. Covering topics from Cognitive Psychology to Artificial Intelligence to Neuroscience to Urban Studies to Evolution and all that is in between, it is the definitive resource for undergraduates, graduate students and researchers.