Is Brain Amyloid Production a Cause or a Result of Dementia of The Alzheimer's Type?

Center for Alzheimer's Disease and Related Disorders, Southern Illinois University School of Medicine, Carbondale, IL 62794, USA.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 01/2010; 22(2):393-9. DOI: 10.3233/JAD-2010-100846
Source: PubMed


The amyloid cascade hypothesis has guided much of the research into Alzheimer's disease (AD) over the last 25 years. We argue that the hypothesis of amyloid-β (Aβ) as the primary cause of dementia may not be fully correct. Rather, we propose that decline in brain metabolic activity, which is tightly linked to synaptic activity, actually underlies both the cognitive decline in AD and the deposition of Aβ. Aβ may further exacerbate metabolic decline and result in a downward spiral of cognitive function, leading to dementia. This novel interpretation can tie the disparate risk factors for dementia to a unifying hypothesis and present a roadmap for interventions to decrease the prevalence of dementia in the elderly population.

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Available from: Gregory J Brewer, Dec 23, 2014
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    • "The definitive diagnosis of some AD cases in the present study (those from SIU AD center) was established by standard postmortem pathological evaluation (Struble et al., 2010). We checked AD-like neuropathology in all human brain samples using Bielschowsky stain and immunolabeling for A∃ and p-tau. "
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    ABSTRACT: Deposition of β -amyloid (Aβ) peptides, cleavage products of β-amyloid precursor protein (APP) by β-secretase-1 (BACE1) and γ-secretase, is a neuropathological hallmark of Alzheimer's disease (AD). γ-Secretase inhibition is a therapeutical anti-Aβ approach, although changes in the enzyme's activity in AD brain are unclear. Cerebrospinal fluid (CSF) Aβ peptides are thought to derive from brain parenchyma and thus may serve as biomarkers for assessing cerebral amyloidosis and anti-Aβ efficacy. The present study compared active γ-secretase binding sites with Aβ deposition in aged and AD human cerebrum, and explored the possibility of Aβ production and secretion by the choroid plexus (CP). The specific binding density of [(3) H]-L-685,458, a radiolabeled high-affinity γ-secretase inhibitor, in the temporal neocortex and hippocampal formation was similar for AD and control cases with similar ages and post-mortem delays. The CP in post-mortem samples exhibited exceptionally high [(3) H]-L-685,458 binding density, with the estimated maximal binding sites (Bmax) reduced in the AD relative to control groups. Surgically resected human CP exhibited APP, BACE1 and presenilin-1 immunoreactivity, and β-site APP cleavage enzymatic activity. In primary culture, human CP cells also expressed these amyloidogenic proteins and released Aβ40 and Aβ42 into the medium. Overall, our results suggest that γ-secretase activity appears unaltered in the cerebrum in AD and is not correlated with regional amyloid plaque pathology. The CP appears to be a previously unrecognised non-neuronal contributor to CSF Aβ, probably at reduced levels in AD.
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