Posted 7 April 2007
Chronic Stress Hypothesis of AD
By Tohru Hasegawa
Saga Woman Junior College, Saga, Japan
Recently, many papers have reported on the physiological functions of amyloid-β and amyloid precursor protein (APP). One of its functions is of importance for synaptic plasticity. Extracellular amyloid-β may suppress synaptic plasticity or inhibit long-term potentiation (LTP) from outside the cell (1,2). LTP is now considered the molecular basis of memory (3). I propose that amyloid-β may induce the inhibition or loss of memory through inhibition of LTP. It is a common experience that unimportant memories are easily forgotten. In particular, I propose that suppression of LTP by amyloid-β induces a kind of physiological forgetfulness. Previous studies have shown that people who cannot forget and remember every detail have difficulty interpreting and making sense of the world. They may fit into this hypothesis, and may have decreased amyloid-β levels compared with people with normal memory.
Normal brain cells release amyloid-β. The extracellular effect of amyloid-β on LTP suppression is a known physiological process (1). We found that homocysteic acid (HA), a known oxidative metabolite of homocysteine, induces amyloid-β accumulation in neuronal cells (4), which means that the physiological function of amyloid-β is inhibited. In fact, HA levels were observed in 3xTg-AD model mice (4#) at 4 months of age, when intraneuronal amyloid-β was observed in the hippocampus of these mice. At 6 months of age, these model mice showed memory impairment. A higher level of HA was observed compared with control mice in brain extract. This implies that HA may be active in the accumulation of amyloid-β in vivo and is related to memory impairment and pathological changes in Alzheimer disease (AD). Frank LaFerla observed glucocorticoid-induced amyloid-β accumulation in these mice (4##). Glucocorticoid increases β-adrenergic activity and consequently induces HA release from astrocytes (8).
HA is known to induce seizures in immature rats (5). Seizures induce strong LTP (6). Hence, it is suggested that HA may induce strong LTP. From our observations, it is clear that HA induces the accumulation of amyloid-β within cells and may induce strong LTP by inhibiting the physiological function of amyloid-β, and this may induce seizures in immature rats. Phinney et al. reported that a subpopulation of APP-null transgenic model mice had seizures (7). This indicates that a lower level of amyloid-β induced strong LTP, that is, seizures. The FAD literature reports that some cases of FAD caused by APP mutations also have seizures. They have abundant amyloid pathology at autopsy. Perhaps too much Aβ and no Aβ both can lead to seizures.
Astrocytes are known to release HA under stress (8). The released HA stimulates glutamate receptors, such as the NMDA receptor and the metabotropic glutamate receptor of the neuron. This induces glutamate signaling and leads to accumulation of amyloid-β from outside the cell or inhibits the release of amyloid-β into the extracellular space. Consequently, HA promotes the intraneuronal accumulation of amyloid-β, which in cooperation with the glutamate signal induces strong LTP. We usually experience very strong emotions in a stressful situation; that is, we experience unforgettable memories in a stressful situation. For example, in the U.S., most people remember precisely where they were and what they were doing when President Kennedy was shot or when the twin towers came down. Sometimes we experience post-traumatic stress disorder (PTSD) following strong stress. PTSD may induce strong LTP (9). Blundell et al. suggested that HA (an NMDA agonist) is involved in PTSD after strong stress (10). In this case, the HA level may not be high enough to induce a seizure. In addition, Francis et al. reported that the HA level was increased under emotional depression (11). Thus, emotional memory enhancement, such as in PTSD or as induced by depression, may involve HA, which induces strong LTP and the accumulation of amyloid-β in neuronal cells.
The situation is different in elderly people. Prolonged stress in the elderly may induce neurodegenerative diseases such as AD, as reported by Charles et al. (12). The reason for AD in the elderly because of prolonged stress is not known, and therefore more attention toward another aspect of HA toxicity is needed. Plasma homocysteine levels increase with age (13), thereby producing HA. The exact metabolism of HA is still not known, but it is certain that HA is produced from homocysteine, because methotrexate treatment leads to higher homocysteine-induced HA production (14). Because homocysteine levels increase with age, it is possible that elderly people have high HA levels. There is a large literature on homocysteine and dementia, and we enjoyed the Alzforum Live Discussion.
We observed that in the presence of excess methionine, HA induced α-synuclein protein in cultured cells, suggesting a hypermethylation model in vivo. Hypermethylation is typically observed in the aging process (15). We conducted this experiment because it is known that homocysteine is a risk factor for Parkinson disease; however, a direct relation between homocysteine and the disease process was not observed. Thus, it is possible that HA induces α-synuclein. Indeed, we observed the α-synuclein protein (Medical Hypothesis in press). In a review, Geddes reports that α-synuclein induced tau pathology (16). We have shown that HA promoted the accumulation of amyloid-β in cells; also, HA produced aggregated α-synuclein in the presence of amyloid-β and consequently impaired cell function (4). LTP is inhibited by deficient cellular function, which means that memories cannot be formed. In fact, there is confusion of memories in the early stages of AD. Finally, the aggregated α-synuclein induces tau pathology (16), which induces cell death.
In conclusion, we propose that HA induces Alzheimer pathology in elderly people because of prolonged stress. That is, when HA accumulates amyloid-β into the neuronal cell from outside the cell, the physiological function of amyloid-β will be inhibited. But HA also induces strong LTP, and the physiological function of amyloid-β will thus be stimulated by HA toxicity. This induces neurons to release more amyloid-β in an effort to suppress the strong HA-induced LTP, and it consequently induces amyloid-β aggregation to form plaque. Surely the entire situation will prove to be more complex than we have outlined here, but the essence of amyloid plaque formation may be what we hypothesize.