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 genotype.

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 compounds.

Post-mortem brain tissue cultures from elderly control subjects and patients with a neurodegenerative disease.

Aging may be viewed as a progressive loss of normal biological function. Due to complex genetic and environmental interactions, the sequence of functional impairment shows a high degree of individual variability. In humans life style and health care have an additional influence on the aging process. To study aging and age-related disorders of the human nervous system, brain tissue that has undergone aging and pathological alterations can provide valuable study material. Recently, we have shown that adult human postmortem brain tissue can be cultured and experimentally manipulated. This approach permits the study of cellular aspects of human neuronal aging and neurodegenerative processes and complements those existing research methods such as in vivo imaging (MRI, PET, etc.) and fixed or frozen postmortem brain tissue examination.

Tissue cultures from adult human postmortem subcortical brain areas.

Animal models used to study human aging and neurodegeneration do not display all symptoms of these processes as they are found in humans. Recently, we have shown that many cells in neocortical slices from adult human postmortem brain may survive for extensive periods in vitro. Such cultures may enable us to study age and disease related processes directly in human brain tissue. Here, we present observations on subcortical brain tissue.

Brain aging and Alzheimer's disease; use it or lose it.

(1) Alzheimer's disease is a multifactorial disease in which age and APOE-epsilon 4 are important risk factors. (2) The neuropathological hallmarks of AD, i.e. amorphous plaques, neuritic plaques (NPs), pretangles, neurofibrillary tangles (NFT) and cell death are not part of a single pathogenetic cascade but may occur independently. (3) In brain areas where classical AD changes, i.e. NPs and NFTs, are present, such as the CA1 area of the hippocampus, the nucleus basalis of Meynert and the tuberomamillary nucleus, a decreased metabolic rate is found. The decreased metabolic rate appears not to be induced by the presence of pretangles, NFT or NPs. (4) Decreased metabolic rate may precede cognitive impairment and is thus an early occurring hallmark of AD, which, in principle, may be reversible. The observation that the administration of glucose or insulin enhances memory in AD patients also supports the view that AD has a metabolic basis. (5) Moreover, several observations in postmortem brain indicate that activated neurons are better able to withstand aging and AD, a phenomenon paraphrased by us as 'use it or lose it'. (6) It is, therefore, attractive to direct the development of therapeutic strategies towards restimulation of neuronal metabolic rate in order to improve cognition and other symptoms in AD. A number of pharmacological and non-pharmacological studies support the concept that activation 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 may be restimulated in AD patients by exposing them to more light or transcutaneous nerve stimulation. A procedure has been developed to culture human postmortem brain tissue that allows testing of the efficacy of putative stimulatory compounds such as neurotrophins.

Excitability and branching of neuroendocrine cells during reproductive senescence.

In the mollusc Lymnaea stagnalis, neuroendocrine caudodorsal cells (CDCs) were studied physiologically and morphologically from egg layers (EL) (aged 154-400), and animals 4 weeks (CEL-4) (342-455 days), and 8 weeks (CEL-8) (477-660 days) after production of their last egg mass. After recording chemical transmission, electrical coupling and stimulation induced afterdischarges (ADs), CDCs then were filled with Lucifer Yellow. Based on the axonal branching revealed by Lucifer Yellow, CDCs were classified as extensively, moderately, or minimally branched. In EL-CDCs, induction of AD activity, which normally (9) precedes egg-laying, only was initiated in the resting state. CEL-4 CDCs exhibited ADs whereas CEL-8 CDCs did not. CEL-8 CDCs exhibited significantly reduced chemical and electrical transmission, and CEL-4 CDCs did not differ from resting state EL-CDCs. CDC branching was significantly reduced with both increasing age and declining egg-laying. Minimally branched CDCs most frequently failed to exhibit an AD and exhibited reduced electrical coupling. We conclude that both physiology and morphology of CDCs are related to age and reproductive state.

Aggravated decrease in the activity of nucleus basalis neurons in Alzheimer's disease is apolipoprotein E-type dependent.

As reported before, the metabolic activity of nucleus basalis neurons is reduced significantly in Alzheimer patients. Because the apolipoprotein E (ApoE) epsilon4 genotype is a major risk factor for Alzheimer's disease (AD), we determined whether the decrease in metabolic activity in nucleus basalis neurons in AD is ApoE-type dependent. The size of the Golgi apparatus (GA) was determined as a measure of neuronal metabolic activity in 30 controls and 41 AD patients with a known ApoE genotype by using an image analysis system in the nucleus basalis of Meynert. A polyclonal antibody directed against MG-160, a sialoglycoprotein of the GA, was used to visualize this organelle. There was a very strong reduction in the size of the GA in the nucleus basalis of AD patients. Furthermore, a strong and significant extra reduction in the size of the GA was found in the nucleus basalis neurons of AD patients with either one or two ApoE epsilon4 alleles compared with Alzheimer patients without ApoE epsilon4 alleles. Our data show that the decreased activity of nucleus basalis neurons in AD is ApoE epsilon4 dependent and suggest that ApoE epsilon4 participates in the pathogenesis of AD by decreasing neuronal metabolism.