Abstract
It is currently thought that the dementia of Alzheimer’s disease is due to the neurotoxicity of the deposits or aggregates of amyloid-β (Aβ) in the extracellular space of the cerebral cortex. This model has been widely criticized because there is a poor correlation between deposits and dementia. Others have questioned whether Aβ is truly neurotoxic. Yet, in spite of these concerns, the search for therapeutic agents has been based on the development of mouse models transfected with mutant genes associated in humans with early onset Alzheimer’s disease. A major limitation of these models is that although they exhibit many of the pathological and clinical manifestation of the human disease, the bulk of individuals who develop the dementia of Alzheimer’s disease have none of these mutant genes. Furthermore, nine clinical trials of drugs that were effective in transgenic mice failed to show any benefit in patients. Finally, a major unresolved issue with the Aβ model is that since Aβ is produced in everyone, why are deposits only seen in the elderly? This issue must be resolved if we are to understand the etiology of the disease and develop test systems for both diagnosis and drug discovery. Published studies from my laboratory demonstrate that in human cerebrospinal fluid immunoreactive Aβ is only present as a complex with two chaperones, ERp57 and calreticulin and is N-glycosylated. This complex formation is catalyzed by the posttranslational protein processing system of the endoplasmic reticulum (ER). Others have reported that in plaque Aβ is present only as the naked peptide. Together these results suggest that both plaque and dementia are secondary to an age related decline in the capacity of the ER to catalyze protein, posttranslational processing. Since the synaptic membrane proteins necessary for a functioning memory are also processed in the ER, these findings would suggest that the loss of cognition is due to a decline in the capacity of the neuron to produce and maintain functioning synapses. Work from my laboratory and from others further indicate that the components of the ER, posttranslational, protein processing pathway do dramatically decline with age. These data suggest that this decline may be found in all cells and could account not only for the dementia of Alzheimer’s disease, but also for many of the other manifestations of the aging process. These observations also suggest that declining ER function has a role in two well-recognized phenomena associated with aging: a loss of mitochondrial function and a decrease in myelin. Finally, based on this paradigm I propose new cellular and animals models for high-throughput screening for drug discovery.
Highlights
It is currently thought that the dementia of Alzheimer’s disease is due to the neurotoxicity of the deposits or aggregates of amyloid-β (Aβ) in the extracellular space of the cerebral cortex
In light of the similar pathology observed between the familial forms and the sporadic disease, many workers have developed transgenic mouse models in which the animals were transfected with mutant forms of the amyloid precursor protein (APP) and/or presenilins 1 and 2
THE EFFECT OF AGE ON THE COMPONENTS OF THE endoplasmic reticulum (ER), POSTTRANSLATIONAL, PROTEIN PROCESSING PATHWAY In light of these findings we hypothesized that the dementia seen in late onset Alzheimer’s disease is due to a decline in the capacity of the neurons to catalyze the ER, posttranslational, protein processing of the synaptic membrane proteins that are necessary for a functioning memory (Erickson et al, 2005)! In support of this hypothesis we found that ERp57 does decline with age (Figure 8; Erickson et al, 2006)
Summary
It is currently thought that the dementia of Alzheimer’s disease is due to the neurotoxicity of the deposits or aggregates of amyloid-β (Aβ) in the extracellular space of the cerebral cortex. In many of the transgenic mouse studies, elderly animals showed cognitive improvement when given some of these agents (Imbimbo et al, 2012) In all of these trials only solanezumab gave even the faintest hope of slowing this decline. Even this agent failed to meet the primary end points, and the noted benefit was only seen after combining the results of subjects with early disease in the two trials of the drug, suggesting that the effect may not have been sufficiently robust to be of clinical significance (Doody, 2012). This would seem to be a somewhat hazardous approach for the long term treatment of patients with cognitive impairment, since knocking out BACE1 has been shown to lead to
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