Alzheimer's Disease (AD) is characterized by cerebral accumulation of ␤-amyloid peptides (A␤), which are proteolytically derived from ␤-amyloid precursor protein (␤APP). ␤APP metabolism is highly regulated via various signal transduction systems, e.g., several serine/threonine kinases and phosphatases. Several growth factors known to act via receptor tyrosine kinases also have been demonstrated to regulate s␤APP secretion. Among these receptors, insulin and insulin-like growth factor-1 receptors are highly expressed in brain, especially in hippocampus and cortex. Emerging evidence indicates that insulin has important functions in brain regions involved in learning and memory. Here we present evidence that insulin significantly reduces intracellular accumulation of A␤ and that it does so by accelerating ␤APP/A␤ trafficking from the transGolgi network, a major cellular site for A␤ generation, to the plasma membrane. Furthermore, insulin increases the extracellular level of A␤ both by promoting its secretion and by inhibiting its degradation via insulin-degrading enzyme. The action of insulin on ␤APP metabolism is mediated via a receptor tyrosine kinase/mitogen-activated protein (MAP) kinase kinase pathway. The results suggest cell biological and signal transduction mechanisms by which insulin modulates ␤APP and A␤ trafficking in neuronal cultures. Key words: ␤-amyloid; ␤-amyloid precursor protein; insulin; MAPK; Alzheimer's disease; diabetes mellitus; intracellular trafficking; endoplasmic reticulum; trans-Golgi network; plasma membraneNeuropathological hallmarks of Alzheimer's Disease (AD) include deposition of ␤-amyloid (A␤) plaques, neurofibrillary tangles, and neuronal cell loss in vulnerable brain regions. Plaques contain an aggregated population of heterogeneous A␤ peptides derived from ␤-amyloid precursor protein (␤APP). Full-length ␤APP undergoes proteolytic ␤-secretase and ␥-secretase activities to generate A␤40 and A␤42 peptides, the predominant A␤ variants. In addition to these amyloid-generating activities, fulllength ␤APP can undergo alternative processing by an enzymatic activity termed "␣-secretase" that cleaves within the A␤ region. This activity releases a soluble fragment (s␤APP␣) extracellularly and precludes A␤ formation. Several studies indicate that A␤ is toxic to neurons. Accumulation of A␤ peptides within the brain is believed to initiate the pathological cascade culminating in clinical AD, a hypothesis supported by the development of early-onset familial AD (FAD) within pedigrees harboring autosomal dominant gene mutations in ␤APP that lead to the excessive generation of A␤ (for review, see Selkoe, 1998). Cell biological studies have demonstrated that both A␤40 and A␤42 are produced intracellularly (Cook et al

Epidemiological, clinical and experimental evidence suggests a link between type 2 diabetes and Alzheimer's disease (AD). Insulin modulates metabolism of ␤-amyloid precursor protein (APP) in neurons, decreasing the intracellular accumulation of ␤-amyloid (A␤) peptides, which are pivotal in AD pathogenesis. The present study investigates whether the widely prescribed insulin-sensitizing drug, metformin (Glucophage R ), affects APP metabolism and A␤ generation in various cell models. We demonstrate that metformin, at doses that lead to activation of the AMP-activated protein kinase (AMPK), significantly increases the generation of both intracellular and extracellular A␤ species. Furthermore, the effect of metformin on A␤ generation is mediated by transcriptional up-regulation of ␤-secretase (BACE1), which results in an elevated protein level and increased enzymatic activity. Unlike insulin, metformin exerts no effect on A␤ degradation. In addition, we found that glucose deprivation and various tyrphostins, known inhibitors of insulin-like growth factors/insulin receptor tyrosine kinases, do not modulate the effect of metformin on A␤. Finally, inhibition of AMP-activated protein kinase (AMPK) by the pharmacological inhibitor Compound C largely suppresses metformin's effect on A␤ generation and BACE1 transcription, suggesting an AMPK-dependent mechanism. Although insulin and metformin display opposing effects on A␤ generation, in combined use, metformin enhances insulin's effect in reducing A␤ levels. Our findings suggest a potentially harmful consequence of this widely prescribed antidiabetic drug when used as a monotherapy in elderly diabetic patients. A lzheimer's disease (AD) is a devastating neurodegenerative disorder, with aging, genetic, and environmental factors contributing to its development and progression. AD is not only characterized by pathological deposition of A␤ peptides and neurofibrillary tangles but is also associated with microgliamediated inflammation and dysregulated lipid homeostasis and glucose metabolism. Amyloid peptides are derived from sequential proteolytic cleavages of full-length amyloid precursor protein (APP) by ␤-secretase (BACE1) and ␥-secretase. Full-length APP can undergo alternative processing by ␣-secretase, releasing a soluble fragment (sAPP␣) extracellularly, which precludes A␤ formation. Compelling evidence indicates that A␤, especially the oligomers, are toxic to neurons; excessive generation and accumulation of A␤ peptides in neurons is believed to initiate the pathological cascade in AD (1-3).Epidemiological studies strongly suggest that metabolic defects correlate with the functional alterations associated with aging of the brain and with AD pathogenesis (4-11). The vast majority of AD cases are late onset and sporadic in origin with aging being the most profound risk factor. Insulin signaling is known to be involved in the process of brain aging (12)(13)(14)(15)(16)(17)(18)(19)(20). Insulin dysfunction/resistance in diabetes mellitus (DM) is not only a common syndrome ...

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Down syndrome (DS) patients exhibit abnormalities of hippocampal-dependent explicit memory, a feature that is replicated in relevant mouse models of the disease. Adult hippocampal neurogenesis, which is impaired in DS and other neuropsychiatric diseases, plays a key role in hippocampal circuit plasticity and has been implicated in learning and memory. However, it remains unknown whether increasing adult neurogenesis improves hippocampal plasticity and behavioral performance in the multifactorial context of DS. We report that, in the Ts65Dn mouse model of DS, chronic administration of lithium, a clinically used mood stabilizer, promoted the proliferation of neuronal precursor cells through the pharmacological activation of the Wnt/ β-catenin pathway and restored adult neurogenesis in the hippocampal dentate gyrus (DG) to physiological levels. The restoration of adult neurogenesis completely rescued the synaptic plasticity of newborn neurons in the DG and led to the full recovery of behavioral performance in fear conditioning, object location, and novel object recognition tests. These findings indicate that reestablishing a functional population of hippocampal newborn neurons in adult DS mice rescues hippocampal plasticity and memory and implicate adult neurogenesis as a promising therapeutic target to alleviate cognitive deficits in DS patients.

Chromosomal rearrangements with duplication of the lamin B1 (LMNB1) gene underlie autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), a rare neurological disorder in which overexpression of LMNB1 causes progressive central nervous system demyelination. However, we previously reported an ADLD family (ADLD-1-TO) without evidence of duplication or other mutation in LMNB1 despite linkage to the LMNB1 locus and lamin B1 overexpression. By custom array-CGH, we further investigated this family and report here that patients carry a large (∼660 kb) heterozygous deletion that begins 66 kb upstream of the LMNB1 promoter. Lamin B1 overexpression was confirmed in further ADLD-1-TO tissues and in a postmortem brain sample, where lamin B1 was increased in the frontal lobe. Through parallel studies, we investigated both loss of genetic material and chromosomal rearrangement as possible causes of LMNB1 overexpression, and found that ADLD-1-TO plausibly results from an enhancer adoption mechanism. The deletion eliminates a genome topological domain boundary, allowing normally forbidden interactions between at least three forebrain-directed enhancers and the LMNB1 promoter, in line with the observed mainly cerebral localization of lamin B1 overexpression and myelin degeneration. This second route to LMNB1 overexpression and ADLD is a new example of the relevance of regulatory landscape modifications in determining Mendelian phenotypes.

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