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 ...…”

The effectiveness and safety of Kami Guibi-tang for mild cognitive impairment: study protocol of a pilot, randomized, placebo-controlled, double-blind trial

“…Alzheimer’s disease has become one of the most serious health concerns, due to increasing life span and aging populations worldwide. The disease is a chronic, progressive neurodegenerative disorder, characterized by pathological changes including neuritic plaques and neurofibrillary tangles, which accumulate years before clinical symptoms manifest [15]. Early treatment of MCI patients could halt or slow down irreversible progression of neurodegeneration to AD [16].…”

MRZ-99030 – A novel modulator of Aβ aggregation: I – Mechanism of action (MoA) underlying the potential neuroprotective treatment of Alzheimer's disease, glaucoma and age-related macular degeneration (AMD)

“…The precise aetiology of AD is still not fully clarified, but is known to be complex and multifactorial, with a notable overlap between familial and non-familial forms but also with different forms of dementia such as vascular dementia. The neurodegeneration seen in AD involves early synaptotoxicity and loss of neuropil, neurotransmitter disturbances, accumulation of extracellular b-amyloid (Ab) deposits (amyloid/senile plaques) and intracellular neurofibrils (neurofibrillary tangles, NFTs), gliosis and only at later stages overt loss of neurons and associated brain atrophy (Bell and Claudio Cuello, 2006;Citron, 2010;Heininger, 1999;Yankner, 1996). At early stages of the disease, the entorhinal cortex and hippocampus are particularly affected and this is associated with deficits in cognition/memory (Braak et al, 1993).…”