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.
    European Journal of Neuroscience 02/2013; 38(2). DOI:10.1111/ejn.12159 · 3.18 Impact Factor
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    • "Alzheimer's disease (AD) and chronic temporal lobe epilepsy (TLE) are classified as two distinct neurological disorders according to their major presenting symptoms. However, they share many pathological features including temporal lobe atrophy, neuronal death, gliosis, neuritic alterations and inflammation [1],[2],[3],[4],[5],[6],[7],[8],[9]. Further, temporal lobe hypometabolism is a premortem feature of AD, as it is for TLE during the interictal phase [10],[11],[12]. "
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    ABSTRACT: The comorbidity between epilepsy and Alzheimer's disease (AD) is a topic of growing interest. Senile plaques and tauopathy are found in epileptic human temporal lobe structures, and individuals with AD have an increased incidence of spontaneous seizures. However, why and how epilepsy is associated with enhanced AD-like pathology remains unknown. We have recently shown β-secretase-1 (BACE1) elevation associated with aberrant limbic axonal sprouting in epileptic CD1 mice. Here we sought to explore whether BACE1 upregulation affected the development of Alzheimer-type neuropathology in mice expressing mutant human APP, presenilin and tau proteins, the triple transgenic model of AD (3×Tg-AD). 3×Tg-AD mice were treated with pilocarpine or saline (i.p.) at 6-8 months of age. Immunoreactivity (IR) for BACE1, β-amyloid (Aβ) and phosphorylated tau (p-tau) was subsequently examined at 9, 11 or 14 months of age. Recurrent convulsive seizures, as well as mossy fiber sprouting and neuronal death in the hippocampus and limbic cortex, were observed in all epileptic mice. Neuritic plaques composed of BACE1-labeled swollen/sprouting axons and extracellular AβIR were seen in the hippocampal formation, amygdala and piriform cortices of 9 month-old epileptic, but not control, 3×Tg-AD mice. Densities of plaque-associated BACE1 and AβIR were elevated in epileptic versus control mice at 11 and 14 months of age. p-Tau IR was increased in dentate granule cells and mossy fibers in epileptic mice relative to controls at all time points examined. Thus, pilocarpine-induced chronic epilepsy was associated with accelerated and enhanced neuritic plaque formation and altered intraneuronal p-tau expression in temporal lobe structures in 3×Tg-AD mice, with these pathologies occurring in regions showing neuronal death and axonal dystrophy.
    PLoS ONE 11/2012; 7(11):e48782. DOI:10.1371/journal.pone.0048782 · 3.23 Impact Factor
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    Journal of Alzheimer's disease: JAD 01/2011; 26 Suppl 3:1-27. DOI:10.3233/JAD-2011-0073 · 4.15 Impact Factor
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