Contrary to common concepts, the brain in Alzheimer's disease (AD) does not follow a suicide but a rescue program. Widely shared features of metabolism in starvation, hibernation and various conditions of energy deprivation, e.g. ischemia, allow the definition of a deprivation syndrome which is a phylogenetically conserved adaptive response to energetic stress. It is characterized by hypometabolism, oxidative stress and adjustments of the glucose-fatty acid cycle. Cumulative evidence suggests that the brain in aging and AD actively adapts to the progressive fuel deprivation. The counterregulatory mechanisms aim to preserve glucose for anabolic needs and promote the oxidative utilization of ketone bodies. The agent mediating the metabolic switch is soluble Abeta which inhibits glucose utilization and stimulates ketone body utilization at various levels. These processes, which are initiated during normal aging, include inhibition of pro-glycolytic neurohormones, cholinergic transmission, and pyruvate dehydrogenase, the key transmitter and effector systems regulating glucose metabolism. Hormonal and effector systems which promote ketone body utilization, such as glucocorticosteroid and galanin activity, GABAergic transmission, nitric oxide, lipid transport, Ca2+ elevation, and ketone body metabolizing enzymes, are enhanced. A multitude of risk factors feed into this pathophysiological cascade at a variety of levels. Taking into account its pleiotropic regulatory actions in the deprivation response, a new name for Abeta is suggested: deprivin. On the other hand, cumulative evidence, taken together compelling, suggests that senile plaques are the dump rather than the driving force of AD. Moreover, the neurotoxic action of fibrillar Abeta is a likely in vitro artifact but does not contribute significantly to the in vivo pathophysiological events. This archaic program, conserved from bacteria to man, aims to ensure the survival of a deprived organism and controls such divergent processes as sporulation, hibernation, aging and aging-related diseases. In contrast to the immature brain, ketone body utilization of the aged brain is no longer sufficient to meet the energetic demands and is later supplemented by lactate, thus recapitulating in reverse order the sequential fuel utilization of the immature brain. The transduction pathways which operate to switch metabolism also convey the programming and balancing of the de-/redifferentiation/apoptosis cell cycle decisions. This encompasses the reiteration of developmental processes such as transcription factor activation, tau hyperphosphorylation, and establishment of growth factor independence by means of Ca2+ set point shift. Thus, the increasing energetic insufficiency results in the progressive centralization of metabolic activity to the neuronal soma, leading to pruning of the axonal/dendritic trees, loss of neuronal polarity, downregulation of neuronal plasticity and, eventually, depending on the Ca2+ -energy-redox homeostasis, degeneration of vulnerable neurons. Finally, it is outlined that genetic (e.g. Down's syndrome, APP and presenilin mutations and apoE4) and environmental risk factors represent progeroid factors which accelerate the aging process and precipitate the manifestation of AD as a progeroid systemic disease. Aging and AD are related to each other by threshold phenomena, corresponding to stage 2, the stage of resistance, and stage 3, exhaustion, of a metabolic stress response.

A unifying hypothesis of Alzheimer's disease. IV. Causation and sequence of events.

In Alzheimer's disease (AD), beta-amyloid (Abeta) is deposited in extracellular matrices, initiating an inflammatory response and compromising cellular integrity. Epidemiological evidence and studies in animal models provide strong evidence that high-saturated-fat and/or cholesterol-rich diets exacerbate cerebral amyloidosis, although the mechanisms for this are unclear. Abeta contains hydrophobic domains and is normally bound to lipid-associated chaperone proteins. In previous studies, we have put forward the notion that Abeta is a regulatory component of postprandial lipoproteins (i.e., chylomicrons) and that aberrations in kinetics may be a contributing risk factor for AD. To explore this further, in this study, we utilized an immunohistochemical approach to determine if Abeta or its precursor protein is expressed in epithelial cells of the small intestine -- the site of chylomicron biogenesis. Wild-type mice were fed a low-fat or a high-fat dietary regime and sacrificed, and their small intestines were isolated. We found that, in mice fed low-fat chow, substantial Abeta/precursor protein was found exclusively in absorptive epithelial cells of the small intestine. In contrast, no Abeta/precursor protein was found in epithelial cells when mice were fasted for 65 h. In addition, we found that a high-fat feeding regime strongly stimulates epithelial cell Abeta/precursor protein concentration. Our findings are consistent with the notion that Abeta may serve as a regulatory apolipoprotein of postprandial lipoproteins.

β-Amyloid or its precursor protein is found in epithelial cells of the small intestine and is stimulated by high-fat feeding

BackgroundPlasma amyloid β-peptide (Aβ) can compromise the blood-brain barrier, contributing to cerebrovascular alterations and amyloid angiopathy in Alzheimer's disease (AD). The objective...

https://journals.sagepub.com/doi/pdf/10.1258/acb.2008.007214

Plasma lipoprotein β-amyloid in subjects with Alzheimer's disease or mild cognitive impairment:

Chylomicron amyloid-beta in the aetiology of Alzheimer’s disease

Background
Amyloid-β is recognized as the major constituent of senile plaque found in subjects with Alzheimer's disease. However, there is increasing evidence that in a physiological context amyloid-β may serve as regulating apolipoprotein, primarily of the triglyceride enriched lipoproteins. To consider this hypothesis further, this study utilized an in vivo immunological approach to explore in lipogenic tissue whether amyloid-β colocalizes with nascent triglyceride-rich lipoproteins.

/pdf/amyloid-b-colocalizes-with-apolipoprotein-b-in-absorptive-14f7yq3t5b.pdf

Amyloid-β colocalizes with apolipoprotein B in absorptive cells of the small intestine

Relationship between lipid metabolism and plasma concentration of amyloid precursor protein and apolipoprotein E

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Relationship between lipid metabolism and plasma concentration of amyloid precursor protein and apolipoprotein E