Loss of M2 muscarine receptors in the cerebral cortex in Alzheimer's disease and experimental cholinergic denervation

Cerebral cortex samples from patients with Alzheimer's disease and from rats after experimental cholinergic denervation of the cerebral cortex exhibited reductions in the presynaptic marker choline acetyltransferase activity and in the number of M2 muscarine receptors, with no change in the number of M1 receptors. These results are in keeping with evidence that M2 receptors function in cholinergic nerve terminals to regulate the release of acetylcholine, whereas M1 receptors are located on postsynaptic cells and facilitate cellular excitation. New M1-selective agonists and M2-selective antagonists directed at post- or presynaptic sites deserve consideration as potential agents for the treatment of the disease.     

脑小血管病与阿尔茨海默病关系研究进展

脑小血管病(CSVD)是一组累及到脑小动脉、微动脉、静脉和毛细血管多病因和病理机制的疾病,主要包含腔隙性脑梗死或腔隙性卒中、脑白质疏松症、Binswanger病和脑微出血.CSVD占全世界卒中的20％,是血管性痴呆和阿尔茨海默病(AD)等认知障碍和痴呆最常见原因.CSVD可促进AD发生,防治脑血管疾病的他汀药物可能对AD有作用.该文着重阐述了AD和CSVD关系,并对AD与腔隙性脑梗死、脑白质疏松症、Binswanger病和脑微出血之间的关系进行了综述,同时分析了CSVD在认知障碍和痴呆发生中的作用.     

Two types of somatostatin receptors differentiated by cyclic somatostatin analogs

Somatostatin receptors in rat brain, pituitary, and pancreas were labeled with two radioiodinated analogs of somatostatins 14 and 28. Two cyclic analogs of somatostatin, SMS201-995 and cyclo(Ala-Cys-Phe-D-Trp-Lys-Thr-Cys), showed biphasic displacement of binding to somatostatin receptors by these radioligands. In contrast, all other somatostatin analogs, including somatostatin-14, competed for the receptor sites with monophasic displacement of radioligand receptor binding. Thus two types of somatostatin receptors were identified. It was found that the pituitary and pancreas have predominantly one type of somatostatin receptor whereas the brain has both, and that different regions of the brain have various proportions of the two types. These findings suggest methods to characterize other types of somatostatin receptors subserving somatostatin's diverse physiological functions, including a potential role in cognitive function and extrapyramidal motor system control.     

Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type

An amyloid protein that precipitates in the cerebral vessel walls of Dutch patients with hereditary cerebral hemorrhage with amyloidosis is similar to the amyloid protein in vessel walls and senile plaques in brains of patients with Alzheimer's disease, Down syndrome, and sporadic cerebral amyloid angiopathy. Cloning and sequencing of the two exons that encode the amyloid protein from two patients with this amyloidosis revealed a cytosine-to-guanine transversion, a mutation that caused a single amino acid substitution (glutamine instead of glutamic acid) at position 22 of the amyloid protein. The mutation may account for the deposition of this amyloid protein in the cerebral vessel walls of these patients, leading to cerebral hemorrhages and premature death.     

Synchronization of unit activity in the cerebral cortex

Simultaneous recording with micropipette electrodes from different units in the cerebral cortex revealed that units seldom fired synchronously. However, there was a temporal relationship in unit firing even when the cortex was "aroused." This relationship was most apparent when strychnine and stimulation were applied to a sensory nerve of an animal asleep or under deep anesthesia.     

Interhemispheric transfer of plasticity in the cerebral cortex

Each half of the body surface is represented topographically in the contralateral cerebral hemisphere. Physiological data are presented showing that homotopic regions of primary somatosensory cortex are linked such that plasticity induced in one hemisphere, in the form of receptive field expansion brought about by a small peripheral denervation, is immediately mirrored in the other hemisphere. Neurons which display the plasticity show no responsiveness to stimulation of the ipsilateral body surface. This suggests that the pathways and mechanisms mediating this transfer are specific to the role of maintaining balance, or integration, between corresponding cortical fields.     

Patterning and plasticity of the cerebral cortex

The cerebral cortex of the human brain is a sheet of about 10 billion neurons divided into discrete subdivisions or areas that process particular aspects of sensation, movement, and cognition. Recent evidence has begun to transform our understanding of how cortical areas form, make specific connections with other brain regions, develop unique processing networks, and adapt to changes in inputs.     

Fate-restricted neural progenitors in the mammalian cerebral cortex

During development of the mammalian cerebral cortex, radial glial cells (RGCs) generate layer-specific subtypes of excitatory neurons in a defined temporal sequence, in which lower-layer neurons are formed before upper-layer neurons. It has been proposed that neuronal subtype fate is determined by birthdate through progressive restriction of the neurogenic potential of a common RGC progenitor. Here, we demonstrate that the murine cerebral cortex contains RGC sublineages with distinct fate potentials. Using in vivo genetic fate mapping and in vitro clonal analysis, we identified an RGC lineage that is intrinsically specified to generate only upper-layer neurons, independently of niche and birthdate. Because upper cortical layers were expanded during primate evolution, amplification of this RGC pool may have facilitated human brain evolution.     

Single-neuron activity and tissue oxygenation in the cerebral cortex

Blood oxygen level-dependent functional magnetic resonance imaging uses alterations in brain hemodynamics to infer changes in neural activity. Are these hemodynamic changes regulated at a spatial scale capable of resolving functional columns within the cerebral cortex? To address this question, we made simultaneous measurements of tissue oxygenation and single-cell neural activity within the visual cortex. Results showed that increases in neuronal spike rate were accompanied by immediate decreases in tissue oxygenation. We used this decrease in tissue oxygenation to predict the orientation selectivity and ocular dominance of neighboring neurons. Our results establish a coupling between neural activity and oxidative metabolism and suggest that high-resolution functional magnetic resonance imaging may be used to localize neural activity at a columnar level.     

Multiple representations of pain in human cerebral cortex

The representation of pain in the cerebral cortex is less well understood than that of any other sensory system. However, with the use of magnetic resonance imaging and positron emission tomography in humans, it has now been demonstrated that painful heat causes significant activation of the contralateral anterior cingulate, secondary somatosensory, and primary somatosensory cortices. This contrasts with the predominant activation of primary somatosensory cortex caused by vibrotactile stimuli in similar experiments. Furthermore, the unilateral cingulate activation indicates that this forebrain area, thought to regulate emotions, contains an unexpectedly specific representation of pain.     

Parvalbumin in most gamma-aminobutyric acid-containing neurons of the rat cerebral cortex

gamma-Aminobutyric acid (GABA) is one of the major inhibitory neurotransmitters in the central nervous system. In the cerebral cortex, GABA-containing cells represent a subpopulation of interneurons. With semithin frozen sections, it is possible to demonstrate that most GABA neurons in the rat somatosensory cortex contain the calcium-binding protein parvalbumin and that parvalbumin is found virtually only in GABA neurons. Parvalbumin seems to influence the electrical properties and enzymatic machinery to modulate neuronal excitability and activity. The specific role of parvalbumin in GABA-containing cortical cells may be related to controlling the effectiveness of their inhibitory action.     

A century of Alzheimer's disease

One hundred years ago a small group of psychiatrists described the abnormal protein deposits in the brain that define the most common neurodegenerative diseases. Over the past 25 years, it has become clear that the proteins forming the deposits are central to the disease process. Amyloid-beta and tau make up the plaques and tangles of Alzheimer's disease, where these normally soluble proteins assemble into amyloid-like filaments. Tau inclusions are also found in a number of related disorders. Genetic studies have shown that dysfunction of amyloid-beta or tau is sufficient to cause dementia. The ongoing molecular dissection of the neurodegenerative pathways is expected to lead to a true understanding of disease pathogenesis.     

Plasticity of hippocampal circuitry in Alzheimer's disease

Two markers of neuronal plasticity were used to compare the response of the human central nervous system to neuronal loss resulting from Alzheimer's disease with the response of rats to a similar neuronal loss induced by lesions. In rats that had received lesions of the entorhinal cortex, axon sprouting of commissural and associational fibers into the denervated molecular layer of the dentate gyrus was paralleled by a spread in the distribution of tritiated kainic acid-binding sites. A similar expansion of kainic acid receptor distribution was observed in hippocampal samples obtained postmortem from patients with Alzheimer's disease. An enhancement of acetylcholinesterase activity in the dentate gyrus molecular layer, indicative of septal afferent sprouting, was also observed in those patients with a minimal loss of cholinergic neurons. These results are evidence that the central nervous system is capable of a plastic response in Alzheimer's disease. Adaptive growth responses occur along with the degenerative events.     

Concurrent overproduction of synapses in diverse regions of the primate cerebral cortex

Synapses develop concurrently and at identical rates in different layers of the visual, somatosensory, motor, and prefrontal areas of the primate cerebral cortex. This isochronic course of synaptogenesis in anatomically and functionally diverse regions indicates that the entire cerebral cortex develops as a whole and that the establishment of cell-to-cell communication in this structure may be orchestrated by a single genetic or humoral signal. This is in contrast to the traditional view of hierarchical development of the cortical regions and provides new insight into the maturation of cortical functions.     

Decreased clearance of CNS beta-amyloid in Alzheimer's disease

Alzheimer's disease is hypothesized to be caused by an imbalance between β-amyloid (Aβ) production and clearance that leads to Aβ accumulation in the central nervous system (CNS). Aβ production and clearance are key targets in the development of disease-modifying therapeutic agents for Alzheimer's disease. However, there has not been direct evidence of altered Aβ production or clearance in Alzheimer's disease. By using metabolic labeling, we measured Aβ42 and Aβ40 production and clearance rates in the CNS of participants with Alzheimer's disease and cognitively normal controls. Clearance rates for both Aβ42 and Aβ40 were impaired in Alzheimer's disease compared with controls. On average, there were no differences in Aβ40 or Aβ42 production rates. Thus, the common late-onset form of Alzheimer's disease is characterized by an overall impairment in Aβ clearance.     

Prostaglandins: localization in subcellular particles of rat cerebral cortex

Homogenates of rat cerebral cortex contain material corresponding to prostaglandins E(1), E(2), F(1)alpha, and F(2)alpha which are concentrated mainly in the light microsomal and mitochondrial fractions. Only the former fraction exhibits significant ability to synthesize prostaglandins E(1) and F(1)alpha from bis-homo-gamma-linolenic acid. After subfractionation of the crude mitochondrial fraction, prostaglandin E and F material is found mainly in the cholinergic and noncholinergic nerve endings. We conclude that the nerve endings are a storage site, whereas the light microsomes are the site of synthesis.     

Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease

We identified axonal defects in mouse models of Alzheimer's disease that preceded known disease-related pathology by more than a year; we observed similar axonal defects in the early stages of Alzheimer's disease in humans. Axonal defects consisted of swellings that accumulated abnormal amounts of microtubule-associated and molecular motor proteins, organelles, and vesicles. Impairing axonal transport by reducing the dosage of a kinesin molecular motor protein enhanced the frequency of axonal defects and increased amyloid-beta peptide levels and amyloid deposition. Reductions in microtubule-dependent transport may stimulate proteolytic processing of beta-amyloid precursor protein, resulting in the development of senile plaques and Alzheimer's disease.