Orly Lazarov

When neurogenesis encounters aging and disease

In this review, we consider the evidence that a reduction in neurogenesis underlies aging-related cognitive deficits and impairments in disorders such as Alzheimers disease (AD). The molecular and cellular alterations associated with impaired neurogenesis in the aging brain are discussed. Dysfunction of presenilin-1, misprocessing of amyloid precursor protein and toxic effects of hyperphosphorylated tau and β-amyloid probably contribute to impaired neurogenesis in AD. Because factors such as exercise, environmental enrichment and dietary energy restriction enhance neurogenesis, and protect against age-related cognitive decline and AD, knowledge of the underlying neurogenic signaling pathways could lead to novel therapeutic strategies for preserving brain function. In addition, manipulation of endogenous neural stem cells and stem cell transplantation, as stand-alone or adjunct treatments, seems promising.

Axonal transport, amyloid precursor protein, kinesin-1, and the processing apparatus: Revisited

The sequential enzymatic actions of β-APP cleaving enzyme 1 (BACE1), presenilins (PS), and other proteins of the γ-secretase complex liberate β-amyloid (Aβ) peptides from larger integral membrane proteins, termed β-amyloid precursor proteins (APPs). Relatively little is known about the normal function(s) of APP or the neuronal compartment(s) in which APP undergoes proteolytic processing. Recent studies have been interpreted as consistent with the idea that APP serves as a kinesin-1 cargo receptor and that PS and BACE1 are associated with the APP-resident membranous cargos that undergo rapid axonal transport. In this report, derived from a collaboration among several independent laboratories, we examined the potential associations of APP and kinesin-1 using glutathione S-transferase pull-down and coimmunoprecipitation assays. In addition, we assessed the trafficking of membrane proteins in the sciatic nerves of transgenic mice with heterozygous or homozygous deletions of APP. In contrast to previous reports, we were unable to find evidence for direct interactions between APP and kinesin-1. Furthermore, the transport of kinesin-1 and tyrosine kinase receptors, previously reported to require APP, was unchanged in axons of APP-deficient mice. Finally, we show that two components of the APP proteolytic machinery, i.e., PS1 and BACE1, are not cotransported with APP in the sciatic nerves of mice. These findings suggest that the hypothesis that APP serves as a kinesin-1 receptor and that the proteolytic processing machinery responsible for generating Aβ is transported in the same vesicular compartment in axons of peripheral nerves requires revision.

Neurogenesis and Alzheimer's disease: At the crossroads

While a massive and progressive neuronal loss in specific areas such as the hippocampus and cortex unequivocally underlies cognitive deterioration and memory loss in Alzheimers disease, noteworthy alterations take place in the neurogenic microenvironments, namely, the subgranule layer of the dentate gyrus and the subventricular zone. Compromised neurogenesis presumably takes place earlier than onset of hallmark lesions or neuronal loss, and may play a role in the initiation and progression of neuropathology in Alzheimers disease. Neurogenesis in the adult brain is thought to play a role in numerous forms and aspects of learning and memory and contribute to the plasticity of the hippocampus and olfactory system. Misregulated or impaired neurogenesis on the other hand, may compromise plasticity and neuronal function in these areas and exacerbate neuronal vulnerability. Interestingly, increasing evidence suggests that molecular players in Alzheimers disease, including PS1, APP and its metabolites, play a role in adult neurogenesis. In addition, recent studies suggest that alterations in tau phosphorylation are pronounced in neurogenic areas, and may interfere with the potential central role of tau proteins in neuronal maturation and differentiation. On the other hand, numerous neurogenic players, such as Notch-1, ErbB4 and L1 are substrates of alpha- beta- and gamma- secretase that play a major role in Alzheimers disease. This review will discuss current knowledge concerning alterations of neurogenesis in Alzheimers disease with specific emphasis on the cross-talk between signaling molecules involved in both processes, and the ways by which familial Alzheimers disease-linked dysfunction of these signaling molecules affect neurogenesis in the adult brain.

Impaired neurogenesis is an early event in the etiology of familial Alzheimer's disease in transgenic mice

Formation of new neurons in the adult brain takes place in the subventricular zone and in the subgranule layer of the dentate gyrus throughout life. Neurogenesis is thought to play a role in hippocampus‐ and olfaction‐dependent learning and memory. However, whether impairments in neurogenesis take place in learning and memory disorders, such as Alzheimers disease, is yet to be established. Importantly, it remains to be elucidated whether neurogenic impairments play a role in the course of the disease or are the result of extensive neuropathology. We now report that transgenic mice harboring familial Alzheimers disease‐linked mutant APPswe/PS1ΔE9 exhibit severe impairments in neurogenesis that are evident as early as 2 months of age. These mice exhibit a significant reduction in the proliferation of neural progenitor cells and their neuronal differentiation. Interestingly, levels of hyperphosphorylated tau, the cytotoxic precursor of the Alzheimers disease hallmark neurofibrillary tangles, are particularly high in the neurogenic niches. Isolation of neural progenitor cells in culture reveals that APPswe/PS1ΔE9‐expressing neurospheres exhibit impaired proliferation and tau hyperphosphorylation compared with wildtype neurospheres isolated from nontransgenic littermates. This study suggests that impaired neurogenesis is an early critical event in the course of Alzheimers disease that may underlie memory impairments, at least in part, and exacerbate neuronal vulnerability in the hippocampal formation and olfaction circuits. Furthermore, impaired neurogenesis is the result of both intrinsic pathology in neural progenitor cells and extrinsic neuropathology in the neurogenic niches. Finally, hyperphosphorylation of the microtubule‐associated protein tau, a critical player in cell proliferation, neuronal maturation, and axonal transport, is a major contributor to impaired neurogenesis in Alzheimers disease.

Non-Cell-Autonomous Effects of Presenilin 1 Variants on Enrichment-Mediated Hippocampal Progenitor Cell Proliferation and Differentiation

Presenilin 1 (PS1) regulates environmental enrichment (EE)-mediated neural progenitor cell (NPC) proliferation and neurogenesis in the adult hippocampus. We now report that transgenic mice that ubiquitously express human PS1 variants linked to early-onset familial Alzheimers disease (FAD) neither exhibit EE-induced proliferation, nor neuronal lineage commitment of NPCs. Remarkably, the proliferation and differentiation of cultured NPCs from standard-housed mice expressing wild-type PS1 or PS1 variants are indistinguishable. On the other hand, wild-type NPCs cocultured with primary microglia from mice expressing PS1 variants exhibit impaired proliferation and neuronal lineage commitment, phenotypes that are recapitulated with mutant microglia conditioned media in which we detect altered levels of selected soluble signaling factors. These findings lead us to conclude that factors secreted from microglia play a central role in modulating hippocampal neurogenesis, and argue for non-cell-autonomous mechanisms that govern FAD-linked PS1-mediated impairments in adult hippocampal neurogenesis.

Complex environment experience rescues impaired neurogenesis, enhances synaptic plasticity, and attenuates neuropathology in familial Alzheimer’s disease-linked APPswe/PS1ΔE9 mice

Experience in complex environments induces numerous forms of brain plasticity, improving structure and function. It has been long debated whether brain plasticity can be induced under neuropathological conditions, such as Alzheimers disease (AD), to an extent that would reduce neuropathology, rescue brain structure, and restore its function. Here we show that experience in a complex environment rescues a significant impairment of hippocampal neurogenesis in transgenic mice harboring familial AD‐linked mutant APPswe/PS1ΔE9. Proliferation of hippocampal cells is enhanced significantly after enrichment, and these proliferating cells mature to become new neurons and glia. Enhanced neurogenesis was accompanied by a significant reduction in levels of hyperphosphorylated tau and oligomeric Aβ, the precursors of AD hallmarks, in the hippocampus and cortex of enriched mice. Interestingly, enhanced expression of the neuronal anterograde motor kinesin‐1 was observed, suggesting enhanced axonal transport in hippocampal and cortical neurons after enrichment. Examination of synaptic physiology revealed that environmental experience significantly enhanced hippocampal long‐term potentiation, without notable alterations in basal synaptic transmission. This study suggests that environmental modulation can rescue the impaired phenotype of the Alzheimers brain and that induction of brain plasticity may represent therapeutic and preventive avenues in AD.—Y.‐S. Hu, P. Xu, G. Pigino, S. T. Brady, J. Larson, O. Lazarov. Complex environment experience rescues impaired neurogenesis, enhances synaptic plasticity, and attenuates neuropathology in familial Alzheimers disease‐linked APPswe/PS1ΔE9 mice. FASEB J. 24, 1667–1681 (2010). www.fasebj.org

Impairments in Fast Axonal Transport and Motor Neuron Deficits in Transgenic Mice Expressing Familial Alzheimer's Disease-Linked Mutant Presenilin 1

Presenilins (PS) play a central role in γ-secretase-mediated processing of β-amyloid precursor protein (APP) and numerous type I transmembrane proteins. Expression of mutant PS1 variants causes familial forms of Alzheimers disease (FAD). In cultured mammalian cells that express FAD-linked PS1 variants, the intracellular trafficking of several type 1 membrane proteins is altered. We now report that the anterograde fast axonal transport (FAT) of APP and Trk receptors is impaired in the sciatic nerves of transgenic mice expressing two independent FAD-linked PS1 variants. Furthermore, FAD-linked PS1 mice exhibit a significant increase in phosphorylation of the cytoskeletal proteins tau and neurofilaments in the spinal cord. Reductions in FAT and phosphorylation abnormalities correlated with motor neuron functional deficits. Together, our data suggests that defects in anterograde FAT may underlie FAD-linked PS1-mediated neurodegeneration through a mechanism involving impairments in neurotrophin signaling and synaptic dysfunction.

Neurogenesis and Inflammation after Ischemic Stroke: What is Known and Where We Go from Here

This review covers the pathogenesis of ischemic stroke and future directions regarding therapeutic options after injury. Ischemic stroke is a devastating disease process affecting millions of people worldwide every year. The mechanisms underlying the pathophysiology of stroke are not fully understood but there is increasing evidence demonstrating the contribution of inflammation to the drastic changes after cerebral ischemia. This inflammation not only immediately affects the infarcted tissue but also causes long-term damage in the ischemic penumbra. Furthermore, the interaction between inflammation and subsequent neurogenesis is not well understood but the close relationship between these two processes has garnered significant interest in the last decade or so. Current approved therapy for stroke involving pharmacological thrombolysis is limited in its efficacy and new treatment strategies need to be investigated. Research aimed at new therapies is largely about transplantation of neural stem cells and using endogenous progenitor cells to promote brain repair. By understanding the interaction between inflammation and neurogenesis, new potential therapies could be developed to further establish brain repair mechanisms.

Axonal degeneration in Alzheimer’s disease: When signaling abnormalities meet the axonal transport system

Alzheimers disease (AD) is characterized by progressive, age-dependent degeneration of neurons in the central nervous system. A large body of evidence indicates that neurons affected in AD follow a dying-back pattern of degeneration, where abnormalities in synaptic function and axonal connectivity long precede somatic cell death. Mechanisms underlying dying-back degeneration of neurons in AD remain elusive but several have been proposed, including deficits in fast axonal transport (FAT). Accordingly, genetic evidence linked alterations in FAT to dying-back degeneration of neurons, and FAT defects have been widely documented in various AD models. In light of these findings, we discuss experimental evidence linking several AD-related pathogenic polypeptides to aberrant activation of signaling pathways involved in the phosphoregulation of microtubule-based motor proteins. While each pathway appears to affect FAT in a unique manner, in the context of AD, many of these pathways might work synergistically to compromise the delivery of molecular components critical for the maintenance and function of synapses and axons. Therapeutic approaches aimed at preventing FAT deficits by normalizing the activity of specific protein kinases may help prevent degeneration of vulnerable neurons in AD.

Molecular Mechanisms of Environmental Enrichment: Impairments in Akt/GSK3β, Neurotrophin-3 and CREB Signaling

Experience of mice in a complex environment enhances neurogenesis and synaptic plasticity in the hippocampus of wild type and transgenic mice harboring familial Alzheimers disease (FAD)-linked APPswe/PS1ΔE9. In FAD mice, this experience also reduces levels of tau hyperphosphorylation and oligomeric β-amyloid. Although environmental enrichment has significant effects on brain plasticity and neuropathology, the molecular mechanisms underlying these effects are unknown. Here we show that environmental enrichment upregulates the Akt pathway, leading to the downregulation of glycogen synthase kinase 3β (GSK3β), in wild type but not FAD mice. Several neurotrophic signaling pathways are activated in the hippocampus of both wild type and FAD mice, including brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF), and this increase is accompanied by the upregulation of the BDNF receptor, tyrosine kinase B (TrkB). Interestingly, neurotrophin-3 (NT-3) is upregulated in the brains of wild type mice but not FAD mice, while insulin growth factor-1 (IGF-1) is upregulated exclusively in the brains of FAD mice. Upregulation of neurotrophins is accompanied by the increase of N-Methyl-D-aspartic acid (NMDA) receptors in the hippocampus following environmental enrichment. Most importantly, we observed a significant increase in levels of cAMP response element- binding (CREB) transcripts in the hippocampus of wild type and FAD mice following environmental enrichment. However, CREB phosphorylation, a critical step for the initiation of learning and memory-required gene transcription, takes place in the hippocampus of wild type but not of FAD mice. These results suggest that experience of wild type mice in a complex environmental upregulates critical signaling that play a major role in learning and memory in the hippocampus. However, in FAD mice, some of these pathways are impaired and cannot be rescued by environmental enrichment.