A mitocentric view of Alzheimer's disease suggests multi-faceted treatments

Abstract

Alzheimer's disease (AD) is defined by senile plaques made of amyloid-beta peptide (Abeta), neurofibrillary tangles made of hyperphosphorylated tau proteins, and memory deficits. Thus, the events initiating the cascade leading to these end points may be more effective therapeutic targets than treating each facet individually. In the small percentage of cases of AD that are genetic (or animal models that reflect this form of AD), the factor initiating AD is clear (e.g., genetic mutations lead to high Abeta1-42 or hyperphosphorylated tau proteins). In the vast majority of AD cases, the cause is unknown. Substantial evidence now suggests that abnormalities in glucose metabolism/mitochondrial function/oxidative stress (GMO) are an invariant feature of AD and occur at an early stage of the disease process in both genetic and non-genetic forms of AD. Indeed, decreases in brain glucose utilization are diagnostic for AD. Changes in calcium homeostasis also precede clinical manifestations of AD. Abnormal GMO can lead to plaques, tangles, and the calcium abnormalities that accompany AD. Abnormalities in GMO diminish the ability of the brain to adapt. Therapies targeting mitochondria may ameliorate abnormalities in plaques, tangles, calcium homeostasis, and cognition that comprise AD.

Figure 1. Critical enzymes of the pentose shunt and the TCA cycle are abnormal in autopsied brains from patients with AD [25, 26]

The figure shows the percent change in AD patients compared to controls. The changes are highly correlated to the clinical dementia rating scores of the patients before they died.

Figure 2. Oxidant treatment can induce diverse changes in metabolic enzymes that resemble the changes in AD brain [80, 136]

Cells with a reduction in one of the three subunits of KGDHC (E2k) were treated with H₂O₂ (See the left half of the figure). KGDHC activity declined while MDH activity increased, which is reminiscent of what happens in AD brains (right half of the figure). Message levels show a similar response to oxidants.

Figure 3. Select oxidants produce changes in ER calcium in control fibroblasts that are reminiscent of those that occur in cells from AD patients [16]

A variety of oxidants were screened for their ability to increase ER calcium in fibroblasts from controls. Select oxidants increase ER calcium. Select antioxidants could block the oxidant induced change in ER calcium (Figure 3A). The same antioxidant brought the exaggerated ER calcium in fibroblasts from AD patients back to control values (Figure 3B).

Figure 3. Select oxidants produce changes in ER calcium in control fibroblasts that are reminiscent of those that occur in cells from AD patients [16]

A variety of oxidants were screened for their ability to increase ER calcium in fibroblasts from controls. Select oxidants increase ER calcium. Select antioxidants could block the oxidant induced change in ER calcium (Figure 3A). The same antioxidant brought the exaggerated ER calcium in fibroblasts from AD patients back to control values (Figure 3B).

Figure 4. Mild impairment of oxidative metabolism exaggerates plaque formation in plaque competent mice

TD diminishes the activities of PDHC, KGDHC and transketolase, which are also diminished in AD. Just ten days of TD leads to a large exacerbation of plaque formation throughout the brain [90].

Figure 5. A mitocentric view of the multifaceted characteristics of AD

Changes in glucose metabolism/mitochondria/oxidative stress (GMO) can be feasibly linked to the cognitive changes, plaque, tangles and calcium abnormalities, which define AD. Once initiated by changes in GMO the other deficits can feedback to exaggerate the abnormalities in GMO creating a vicious cycle. This view of AD suggests treatment of the mitochondria/oxidative stress deficit will correct the others whereas treatments targeted at just one facet will fail.