Amyloid Hypothesis
While there are several hypotheses as to the pathogenesis of Alzheimer's disease, the most widely accepted one is the Amyloid Hypothesis.
This hypothesis proposes that progressive cerebral accumulation of amyloid β-protein (Aβ) initiates a complex multicellular cascade that includes neuritic
dystrophy, microgliosis, astrocytosis, neuronal dysfunction, and the synaptic alterations that result in neurotransmitter deficits and impaired cognitive
functions.
Amyloid beta (Aβ) was first identified in 1984 as the main component of amyloid plaques (Glenner and Wong 1984), and subsequently evidence has accumulated
to suggest that this peptide is the primary reason for neuropathological insult in AD. This was first proposed in 1991 by John Hardy and David Allsop and
several prominent researchers have further substantiated this hypothesis. The hypothesis was also presented by Dr. Dennis Selkoe at the Fifth International
Conference on Alzheimer's disease in Osaka Japan 1996.
The Amyloid Hypothesis suggests that the metabolism of APP is the initiating event in AD pathogenesis, subsequently leading to the aggregation of Aβ,
specifically Aβ42. Transgenic mice models expressing pathogenic mutations of APP (Hsiao et al 1996) and PS1 have increased levels of Aβ and amyloid plaques.
Furthermore, individuals with trisomy 21 (Down’s syndrome, DS) have 3 copies of APP and usually develop advanced AD within the fourth decade of life.
The central observation supporting the amyloid cascade hypothesis is that the vast majority of mutations causing familial AD, including, misense mutations
in APP or Presenelin 1 or 2 genes, increase the relative ratio of fibrillogenic Aβ42 (Tanzi and Bertram 2005) due to a lifelong increase in production of amyloidogenic
Aβ.
That said, it also known that merely less than 10% of AD patients have "familial" AD. In the rest of the patients, termed as having "sporadic" AD, the levels
of production of Aβ are normal. However, it is the failure of clearance mechanisms that leads to an accumulation of toxic forms of Aβ. Thus, Alzheimer's
disease is primarily a "storage" disease (Berislav Zlokovic, 2004). In a majority of patients, Aβ deposition may take decades to develop and may be influenced by lifelong patterns of
impaired Aβ clearance.
In recent years, attention has turned towards soluble, oligomeric and even intracellular Aβ42, rather than insoluble forms of Aβ. Soluble Aβ
levels correlate more strongly with dementia severity. It has been shown that soluble Aβ levels alter hippocampal synaptic efficiency in rats, while increased
expression of Aβ42 in Drosophila induces formation of diffuse amyloid deposits, age-dependent learning defects and extensive neurodegeneration. In addition,
cognitive defects in mice are caused by small oligomeric Aβ assemblies, before Aβ deposition. Soluble and insoluble forms of Aβ exist in the brain in
a dynamic equilibrium (reviewed by Todd Golde 2006).
The Amyloid Hypothesis suggests that the metabolism of APP is the initiating event in AD pathogenesis, subsequently leading to the aggregation of Aβ, specifically Aβ42. Transgenic mice models expressing pathogenic mutations of APP (Hsiao et al 1996) and PS1 have increased levels of Aβ and amyloid plaques. Furthermore, individuals with trisomy 21 (Down’s syndrome, DS) have 3 copies of APP and usually develop advanced AD within the fourth decade of life. The central observation supporting the amyloid cascade hypothesis is that the vast majority of mutations causing familial AD, including, misense mutations in APP or Presenelin 1 or 2 genes, increase the relative ratio of fibrillogenic Aβ42 (Tanzi and Bertram 2005) due to a lifelong increase in production of amyloidogenic Aβ.
That said, it also known that merely less than 10% of AD patients have "familial" AD. In the rest of the patients, termed as having "sporadic" AD, the levels of production of Aβ are normal. However, it is the failure of clearance mechanisms that leads to an accumulation of toxic forms of Aβ. Thus, Alzheimer's disease is primarily a "storage" disease (Berislav Zlokovic, 2004). In a majority of patients, Aβ deposition may take decades to develop and may be influenced by lifelong patterns of impaired Aβ clearance.
In recent years, attention has turned towards soluble, oligomeric and even intracellular Aβ42, rather than insoluble forms of Aβ. Soluble Aβ levels correlate more strongly with dementia severity. It has been shown that soluble Aβ levels alter hippocampal synaptic efficiency in rats, while increased expression of Aβ42 in Drosophila induces formation of diffuse amyloid deposits, age-dependent learning defects and extensive neurodegeneration. In addition, cognitive defects in mice are caused by small oligomeric Aβ assemblies, before Aβ deposition. Soluble and insoluble forms of Aβ exist in the brain in a dynamic equilibrium (reviewed by Todd Golde 2006).