A unifying hypothesis of Alzheimer's disease. II. Pathophysiological processes

Abstract

The age-related loss of hormonal balance puts the homeostatic calcium±energy±antioxidant triangle under stress. The energetic compromise enhances b-amyloid protein formation and tau protein hyperphosphorylation, both cellular stress responses, which may give rise to diuse plaque and neuro®brillary tangle formation during normal ageing. Facilitated by a multitude of risk factors (discussed in part III of this series), the age-related processes lead into the pathophysiological events of Alzheimer's disease (AD). In AD, the hormonal imbalance is further aggravated with progressively detrimental sequelae for the calcium±energy±redox homeostasis and for both amyloid protein precursor and tau protein metabolism. The immune system as an integral component of the neuroendocrine immunological network is subject to the deteriorating endocrinological balance and displays a cellular and humoral acute phase-type reaction. In an orchestrated action, an in¯ammatory response is mounted in which activated micro-and astro-glia and their secreted in¯ammatory mediators and matrix constituents elicit the transformation of diuse into neuritic plaques which, secondarily, may induce further tissue damage. Importantly, the AD brain is characterized by the microglial inability to clear the brain of the deposited material. The pathophysiological processes lead to functional and structural impairments of neuronal plasticity, a compromise of the neuronal network and, eventually, to cell death. Conspicuously, these alterations do not uniformly aect all brain regions but manifest with a temporal and topographical speci®city vulnerable areas and nerve cell populations. Copyright # 1999 John Wiley & Sons, Ltd.KEY WORDS Ð Alzheimer's disease; calcium; energy metabolism; oxidative stress; mitochondria; glucocorticoids; neuropeptide Y; DHEA; oestrogen; melatonin; somatostatin; nerve growth factors; insulin; b-amyloid; tau; immune system; signal transduction; apoptosis; vulnerability AGEING AND ALZHEIMER'S DISEASE In part I of this series it was posited that the agerelated imbalance of neuropeptides and hormones puts the neurons under metabolic stress [Heininger, 1999]. Hence, it is outlined how this compromise of cellular homeostasis may lead to the production of amyloid b-protein (Ab) and hyperphosphorylation of tau protein (P-tau). These processes occur already during normal ageing. Both Ab and senile plaques (SP) as well as P-tau and neuro®brillary tangles (NFT) are found in the normal aged brain in a spatial distribution suggesting their independent formation and potentially representing a preclinical stage of the disease [Beach et al., 1997;Braak and Braak, 1997;Troncoso et al., 1998;Price and Morris, 1999].Nevertheless, since these changes are the hallmark of the pathomorphological diagnosis [Khachaturian, 1985; Ball et al., 1997] and, for the sake of the argument, they have been grouped as pathophysiological AD processes. However, it should be borne in mind that these processes are not ADspeci®c and that only by some additional quantitative...

Localization of the noncovalent binding site between amyloid-β-peptide and oleuropein using electrospray ionization FT-ICR mass spectrometry

“…When OE was added into already digested A␤ samples with trypsin ( Similarly, ESI-MS analysis of the A␤-OE Glu-C digest yielded signals corresponding to the expected A␤ fragments [4 -11], [12][13][14][15][16][17][18][19][20][21][22], and [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] following cleavage at the carboxy-terminus of glutamic acid (E) residues (Table 2), and the noncovalent complexes between OE and the [4 -11] and [12][13][14][15][16][17][18][19][20][21][22] A␤ Glu-C fragments ( Figure 3). Interactions between OE and the partially cleaved peptide fragments [4 -40] and (Table 4) When OE was added into already digested A␤ samples with Glu-C (Table 4), ESI signals corresponded to ...…”

“…Free radical reactions and oxidative stress [28,29], as well as unregulated immune response [30,31], are believed to be key factors for the pathogenesis of AD, whereas recent reports suggested a link between heart disease, hypercholesterolemia, and…”

“…Free radical reactions and oxidative stress [28,29], as well as unregulated immune response [30,31], are believed to be key factors for the pathogenesis of AD, whereas recent reports suggested a link between heart disease, hypercholesterolemia, and AD [32,33]. Thus, the well-documented antioxidant, anti-inflammatory, and antiatherogenic properties of OE may offer a multistage approach against the diverse mechanisms, which are inherent to AD.…”

Noncovalent interaction between amyloid-β-peptide (1–40) and oleuropein studied by electrospray ionization mass spectrometry

“…The circumstantial evidence that cholesterol-related interventions can alter A␤ deposition [33,34], suggest that OE could be promising in the management of AD. Furthermore, the importance of inflammatory processes in the clinical manifestation of AD [9,35], combined with the epidemiological evidence of a protective effect of anti-inflammatory agents [36] against AD, suggest that a polyphenolic natural extract, such as OE, could prove effective against agedependent disorders such as AD. Furthermore, it has been reported that OE and its metabolites could be potent bioactive compounds against contemporary diseases, such as HIV [37], osteoporosis [38], and AD [39].…”

Identification and characterisation of the novel amyloid‐beta peptide‐induced protein p17

“…These peptides are derived from its precursor, the amyloid precursor protein (APP) [3]. A mutation in this gene results in the aberrant production of the neurotoxic Ab [4]. However, the pathways of which Ab achieves neurodegeneration are still unknown.…”