Therapeutic strategies for Alzheimer disease: focus on neuronal reactivation of metabolically impaired neurons

Based on several lines of evidence, it has been hypothesized that decreased neuronal metabolic rate may precede cognitive impairment, contributing to neuronal atrophy as well as reduced neuronal function in Alzheimer disease (AD). Additionally, studies have shown that stimulation of neurons through different mechanisms may protect those cells from the deleterious effects of aging and AD, a phenomenon we paraphrased as "use it or lose it." Therefore, it is attractive to direct the development of therapeutic strategies toward stimulation of metabolic rate/neuronal activity to improve cognition and other symptoms in AD. A number of pharmacological and nonpharmacological approaches discussed here support the concept that stimulation of the brain has beneficial effects and may, to a certain degree, restore several aspects of cognition and other central functions. For instance, the circadian system, which controls the sleep/wake cycle, may be stimulated in AD patients by exposing them to more light or transcutaneous nerve stimulation. We will also discuss a procedure that has been developed to culture human postmortem brain tissue, which allows testing of the efficacy of putative stimulatory compound

ApoE epsilon4 genotype is accompanied by lower metabolic activity in nucleus basalis of Meynert neurons in Alzheimer patients and controls as indicated by the size of the Golgi apparatus

We previously found apolipoprotein (apoE) epsilon4-dependent lower metabolic activity in nucleus basalis of Meynert (NBM) neurons in Alzheimer disease (AD). In the present study we examined the metabolic activity in the NBM of 39 mentally intact control subjects with different APOE genotype. The control subjects had either no AD pathology (Braak stage 0) or the very beginning of AD pathology (Braak stage I-II). We used the Golgi apparatus (GA) size as a measure of neuronal metabolic activity. Control subjects carrying an apoE epsilon4 allele showed reduced neuronal metabolism; they had significantly more neurons with smaller GA sizes compared to control subjects not carrying an apoE epsilon4 allele. Only control subjects not carrying an apoE epsilon4 allele had increased neuronal metabolism in Braak I-II subjects. They had more neurons with larger GA sizes compared to Braak 0 subjects, which may reflect a compensatory mechanism. Our data indicate that APOE epsilon4 may act by a lower neuronal metabolism as a risk factor for cognitive impairment in normal aging and early prodromal AD. As the disease progresses into later stages of AD (Braak V-VI) neuronal metabolism strongly diminishes, resulting in neurons with extremely small GA sizes, irrespective of APOE genotyp

Increased metabolic activity in nucleus basalis of Meynert neurons in elderly individuals with mild cognitive impairment as indicated by the size of the Golgi apparatus.

In this study, we examined the metabolic activity of nucleus basalis of Meynert (NBM) neurons in individuals clinically diagnosed with no cognitive impairment (NCI, n = 8), mild cognitive impairment (MCI, n = 9), and subjects with moderate Alzheimer disease (AD, n = 7). We used Golgi apparatus (GA) size as a measure of neuronal metabolic activity. Subjects with MCI showed increased NBM metabolic activity; they had significantly more neurons with larger GA size as compared with NCI and AD subjects. In contrast, more NBM neurons with extremely small GA sizes, indicating reduced metabolic activity, were seen in AD. When these cases were classified according to their AD pathology (Braak I-II, III-IV, or V-VI), Braak III-IV subjects showed significantly increased GA sizes, comparable with the increase in clinically diagnosed MCI, whereas in Braak V-VI, GA sizes were dramatically reduced. Of all MCI and NCI subjects with similar Braak III-IV pathology, the MCI subjects again had significantly larger GA sizes. The larger NBM neuronal GA size seen in MCI suggests increased metabolic activity, associated with both the clinical progression from NCI to MCI, and with the early stages of AD pathology

Increased metabolic activity in nucleus basalis of Meynert neurons in elderly individuals with mild cognitive impairment as indicated by the size of the Golgi apparatus.

In this study, we examined the metabolic activity of nucleus basalis of Meynert (NBM) neurons in individuals clinically diagnosed with no cognitive impairment (NCI, n = 8), mild cognitive impairment (MCI, n = 9), and subjects with moderate Alzheimer disease (AD, n = 7). We used Golgi apparatus (GA) size as a measure of neuronal metabolic activity. Subjects with MCI showed increased NBM metabolic activity; they had significantly more neurons with larger GA size as compared with NCI and AD subjects. In contrast, more NBM neurons with extremely small GA sizes, indicating reduced metabolic activity, were seen in AD. When these cases were classified according to their AD pathology (Braak I-II, III-IV, or V-VI), Braak III-IV subjects showed significantly increased GA sizes, comparable with the increase in clinically diagnosed MCI, whereas in Braak V-VI, GA sizes were dramatically reduced. Of all MCI and NCI subjects with similar Braak III-IV pathology, the MCI subjects again had significantly larger GA sizes. The larger NBM neuronal GA size seen in MCI suggests increased metabolic activity, associated with both the clinical progression from NCI to MCI, and with the early stages of AD pathology.