Alzheimer Disease: Palop JJ

Palop JJ, Mucke L. · Gladstone Institute of Neurological Disease and Department of Neurology, University of California, San Francisco, CA 94158, USA. · Arch Neurol. · Pubmed #19204149 No free full text.

Abstract: Alzheimer disease (AD) is associated with cognitive decline and increased incidence of seizures. Seizure activity in AD has been widely interpreted as a secondary process resulting from advanced stages of neurodegeneration, perhaps in combination with other age-related factors. However, recent findings in animal models of AD have challenged this notion, raising the possibility that aberrant excitatory neuronal activity represents a primary upstream mechanism that may contribute to cognitive deficits in these models. The following observations suggest that such activity may play a similar role in humans with AD: (1) patients with sporadic AD have an increased incidence of seizures that appears to be independent of disease stage and highest in cases with early onset; (2) seizures are part of the natural history of many pedigrees with autosomal dominant early-onset AD, including those with mutations in presenilin-1, presenilin-2, or the amyloid precursor protein, or with duplications of wild-type amyloid precursor protein; (3) inheritance of the major known genetic risk factor for AD, apolipoprotein E4, is associated with subclinical epileptiform activity in carriers without dementia; and (4) some cases of episodic amnestic wandering and disorientation in AD are associated with epileptiform activity and can be prevented with antiepileptic drugs. Here we review recent experimental data demonstrating that high levels of beta-amyloid in the brain can cause epileptiform activity and cognitive deficits in transgenic mouse models of AD. We conclude that beta-amyloid peptides may contribute to cognitive decline in AD by eliciting similar aberrant neuronal activity in humans and discuss potential clinical and therapeutic implications of this hypothesis.

Palop JJ, Chin J, Mucke L. · Gladstone Institute of Neurological Disease and Department of Neurology, University of California, San Francisco, California 94158, USA. · Nature. · Pubmed #17051202 No free full text.

Abstract: Patients with Alzheimer's disease or other neurodegenerative disorders show remarkable fluctuations in neurological functions, even during the same day. These fluctuations cannot be caused by sudden loss or gain of nerve cells. Instead, it is likely that they reflect variations in the activity of neural networks and, perhaps, chronic intoxication by abnormal proteins that the brain is temporarily able to overcome. These ideas have far-reaching therapeutic implications.

Sanchez-Mejia RO, Newman JW, Toh S, Yu GQ, Zhou Y, Halabisky B, Cissé M, Scearce-Levie K, Cheng IH, Gan L, Palop JJ, Bonventre JV, Mucke L. · Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA. · Nat Neurosci. · Pubmed #18931664 links to  free full text

Abstract: Neuronal expression of familial Alzheimer's disease-mutant human amyloid precursor protein (hAPP) and hAPP-derived amyloid-beta (Abeta) peptides causes synaptic dysfunction, inflammation and abnormal cerebrovascular tone in transgenic mice. Fatty acids may be involved in these processes, but their contribution to Alzheimer's disease pathogenesis is uncertain. We used a lipidomics approach to generate a broad profile of fatty acids in brain tissues of hAPP-expressing mice and found an increase in arachidonic acid and its metabolites, suggesting increased activity of the group IV isoform of phospholipase A(2) (GIVA-PLA(2)). The levels of activated GIVA-PLA(2) in the hippocampus were increased in individuals with Alzheimer's disease and in hAPP mice. Abeta caused a dose-dependent increase in GIVA-PLA(2) phosphorylation in neuronal cultures. Inhibition of GIVA-PLA(2) diminished Abeta-induced neurotoxicity. Genetic ablation or reduction of GIVA-PLA(2) protected hAPP mice against Abeta-dependent deficits in learning and memory, behavioral alterations and premature mortality. Inhibition of GIVA-PLA(2) may be beneficial in the treatment and prevention of Alzheimer's disease.

Meilandt WJ, Yu GQ, Chin J, Roberson ED, Palop JJ, Wu T, Scearce-Levie K, Mucke L. · Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA. · J Neurosci. · Pubmed #18463254 links to  free full text

Abstract: The enkephalin signaling pathway regulates various neural functions and can be altered by neurodegenerative disorders. In Alzheimer's disease (AD), elevated enkephalin levels may reflect compensatory processes or contribute to cognitive impairments. To differentiate between these possibilities, we studied transgenic mice that express human amyloid precursor protein (hAPP) and amyloid-beta (Abeta) peptides in neurons and exhibit key aspects of AD. Met-enkephalin levels in neuronal projections from the entorhinal cortex and dentate gyrus (brain regions important for memory that are affected in early stages of AD) were increased in hAPP mice, as were preproenkephalin mRNA levels. Genetic manipulations that exacerbate or prevent excitotoxicity also exacerbated or prevented the enkephalin alterations. In human AD brains, enkephalin levels in the dentate gyrus were also increased. In hAPP mice, enkephalin elevations correlated with the extent of Abeta-dependent neuronal and behavioral alterations, and memory deficits were reduced by irreversible blockade of mu-opioid receptors with the antagonist beta-funaltrexamine. We conclude that enkephalin elevations may contribute to cognitive impairments in hAPP mice and possibly in humans with AD. The therapeutic potential of reducing enkephalin production or signaling merits further exploration.

Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, Yoo J, Ho KO, Yu GQ, Kreitzer A, Finkbeiner S, Noebels JL, Mucke L. · Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA. · Neuron. · Pubmed #17785178 No free full text.

Abstract: Neural network dysfunction may play an important role in Alzheimer's disease (AD). Neuronal circuits vulnerable to AD are also affected in human amyloid precursor protein (hAPP) transgenic mice. hAPP mice with high levels of amyloid-beta peptides in the brain develop AD-like abnormalities, including cognitive deficits and depletions of calcium-related proteins in the dentate gyrus, a region critically involved in learning and memory. Here, we report that hAPP mice have spontaneous nonconvulsive seizure activity in cortical and hippocampal networks, which is associated with GABAergic sprouting, enhanced synaptic inhibition, and synaptic plasticity deficits in the dentate gyrus. Many Abeta-induced neuronal alterations could be simulated in nontransgenic mice by excitotoxin challenge and prevented in hAPP mice by blocking overexcitation. Aberrant increases in network excitability and compensatory inhibitory mechanisms in the hippocampus may contribute to Abeta-induced neurological deficits in hAPP mice and, possibly, also in humans with AD.

Cheng IH, Scearce-Levie K, Legleiter J, Palop JJ, Gerstein H, Bien-Ly N, Puoliväli J, Lesné S, Ashe KH, Muchowski PJ, Mucke L. · Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA. · J Biol Chem. · Pubmed #17548355 links to  free full text

Abstract: Many proteins suspected of causing neurodegenerative diseases exist in diverse assembly states. For most, it is unclear whether shifts from one state to another would be helpful or harmful. We used mutagenesis to change the assembly state of Alzheimer disease (AD)-associated amyloid-beta (Abeta) peptides. In vitro, the "Arctic" mutation (AbetaE22G) accelerated Abeta fibrillization but decreased the abundance of nonfibrillar Abeta assemblies, compared with wild-type Abeta. In human amyloid precursor protein (hAPP) transgenic mice carrying mutations adjacent to Abeta that increase Abeta production, addition of the Arctic mutation markedly enhanced the formation of neuritic amyloid plaques but reduced the relative abundance of a specific nonfibrillar Abeta assembly (Abeta*56). Mice overexpressing Arctic mutant or wild-type Abeta had similar behavioral and neuronal deficits when they were matched for Abeta*56 levels but had vastly different plaque loads. Thus, Abeta*56 is a likelier determinant of functional deficits in hAPP mice than fibrillar Abeta deposits. Therapeutic interventions that reduce Abeta fibrils at the cost of augmenting nonfibrillar Abeta assemblies could be harmful.

Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H, Yu GQ, Mucke L. · Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA. · Science. · Pubmed #17478722 links to  free full text

Abstract: Many potential treatments for Alzheimer's disease target amyloid-beta peptides (Abeta), which are widely presumed to cause the disease. The microtubule-associated protein tau is also involved in the disease, but it is unclear whether treatments aimed at tau could block Abeta-induced cognitive impairments. Here, we found that reducing endogenous tau levels prevented behavioral deficits in transgenic mice expressing human amyloid precursor protein, without altering their high Abeta levels. Tau reduction also protected both transgenic and nontransgenic mice against excitotoxicity. Thus, tau reduction can block Abeta- and excitotoxin-induced neuronal dysfunction and may represent an effective strategy for treating Alzheimer's disease and related conditions.

Chin J, Massaro CM, Palop JJ, Thwin MT, Yu GQ, Bien-Ly N, Bender A, Mucke L. · Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, California 94158, USA. · J Neurosci. · Pubmed #17360894 links to  free full text

Abstract: Reelin regulates nervous system development and modulates synaptic plasticity in the adult brain. Several findings suggest that alterations in Reelin signaling may contribute to neuronal dysfunction associated with Alzheimer's disease (AD). Cell surface receptors for Reelin, including integrins and very-low-density lipoprotein receptor/apolipoprotein E2 receptor, may be targets of amyloid-beta (Abeta) peptides presumed to play key roles in the pathogenesis of AD. Reelin also regulates the extent of tau phosphorylation. Finally, increased amounts of Reelin fragments have been found in CSF from AD patients, suggesting altered processing of Reelin. We therefore hypothesized that Reelin levels might be altered in the brains of human amyloid precursor protein (hAPP) transgenic mice, particularly in brain regions vulnerable to AD such as hippocampus and entorhinal cortex. Compared with nontransgenic controls, hAPP mice had significantly fewer Reelin-expressing pyramidal cells in the entorhinal cortex, the major population of glutamatergic neurons expressing Reelin in the brain. Western blot analysis of the hippocampus, which receives projections from the entorhinal cortex, revealed significant reductions in Reelin levels. In contrast, the number of Reelin-expressing GABAergic interneurons was not altered in either the entorhinal cortex or the hippocampus. Thus, neuronal expression of hAPP/Abeta is sufficient to reduce Reelin expression in a specific population of entorhinal cortical pyramidal neurons in vivo. Underscoring the relevance of these findings, we found qualitatively similar reductions of Reelin-expressing pyramidal neurons in the entorhinal cortex of AD brains. We conclude that alterations in Reelin processing or signaling may be involved in AD-related neuronal dysfunction.

Chin J, Palop JJ, Puoliväli J, Massaro C, Bien-Ly N, Gerstein H, Scearce-Levie K, Masliah E, Mucke L. · Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158, USA. · J Neurosci. · Pubmed #16237174 links to  free full text

Abstract: Human amyloid precursor protein (hAPP) transgenic mice with high levels of amyloid-beta (Abeta) develop behavioral deficits that correlate with the depletion of synaptic activity-related proteins in the dentate gyrus. The tyrosine kinase Fyn is altered in Alzheimer's disease brains and modulates premature mortality and synaptotoxicity in hAPP mice. To determine whether Fyn also modulates Abeta-induced behavioral deficits and depletions of synaptic activity-dependent proteins, we overexpressed Fyn in neurons of hAPP mice with moderate levels of Abeta production. Compared with nontransgenic controls and singly transgenic mice expressing hAPP or FYN alone, doubly transgenic FYN/hAPP mice had striking depletions of calbindin, Fos, and phosphorylated ERK (extracellular signal-regulated kinase), impaired neuronal induction of Arc, and impaired spatial memory retention. These deficits were qualitatively and quantitatively similar to those otherwise seen only in hAPP mice with higher Abeta levels. Surprisingly, levels of active Fyn were lower in high expresser hAPP mice than in NTG controls and lower in FYN/hAPP mice than in FYN mice. Suppression of Fyn activity may result from dephosphorylation by striatal-enriched phosphatase, which was upregulated in FYN/hAPP mice and in hAPP mice with high levels of Abeta. Thus, increased Fyn expression is sufficient to trigger prominent neuronal deficits in the context of even relatively moderate Abeta levels, and inhibition of Fyn activity may help counteract Abeta-induced impairments.

Cheng IH, Palop JJ, Esposito LA, Bien-Ly N, Yan F, Mucke L. · Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158, USA. · Nat Med. · Pubmed #15502844 No free full text.

Abstract: The Arctic mutation within the amyloid-beta (Abeta) peptide causes Alzheimer disease. In vitro, Arctic-mutant Abeta forms (proto)fibrils more effectively than wild-type Abeta. We generated transgenic mouse lines expressing Arctic-mutant human amyloid precursor proteins (hAPP). Amyloid plaques formed faster and were more extensive in Arctic mice than in hAPP mice expressing wild-type Abeta, even though Arctic mice had lower Abeta(1-42/1-40) ratios. Thus, the Arctic mutation is highly amyloidogenic in vivo.

Chin J, Palop JJ, Yu GQ, Kojima N, Masliah E, Mucke L. · Gladstone Institute of Neurological Disease and Department of Neurology, University of California, San Francisco, California 94141-9100, USA. · J Neurosci. · Pubmed #15140940 links to  free full text

Abstract: Alzheimer's disease (AD), the most common neurodegenerative disorder, results in progressive degeneration of synapses and aberrant sprouting of axon terminals. The mechanisms underlying these seemingly opposing cellular phenomena are unclear. We hypothesized that Fyn kinase may play a role in one or both of these processes because it is increased in AD brains and because it is involved in synaptic plasticity and axonal outgrowth. We investigated the effects of Fyn on AD-related synaptotoxicity and aberrant axonal sprouting by ablating or overexpressing Fyn in human amyloid precursor protein (hAPP) transgenic mice. On the fyn+/+ background, hAPP/amyloid beta peptide (Abeta) decreased hippocampal levels of synaptophysin-immunoreactive presynaptic terminals (SIPTs), consistent with previous findings. On the fyn-/- background, hAPP/Abeta did not affect SIPTs. SIPT reductions correlated with hippocampal Abeta levels in hAPP/fyn+/+, but not hAPP/fyn-/-, mice suggesting that Fyn provides a critical link between hAPP/Abeta and SIPTs. Furthermore, overexpression of Fyn exacerbated SIPT reductions in hAPP mice. We also found that the susceptibility of mice to hAPP/Abeta-induced premature mortality was decreased by Fyn ablation and increased by Fyn overexpression. In contrast, axonal sprouting in the hippocampus of hAPP mice was unaffected. We conclude that Fyn-dependent pathways are critical in AD-related synaptotoxicity and that the pathogenesis of hAPP/Abeta-induced neuronal alterations may be mechanistically heterogenous.

Palop JJ, Jones B, Kekonius L, Chin J, Yu GQ, Raber J, Masliah E, Mucke L. · Gladstone Institute of Neurological Disease and Department of Neurology, University of California, San Francisco, CA 94141, USA. · Proc Natl Acad Sci U S A. · Pubmed #12881482 links to  free full text

Abstract: Transgenic mice expressing human amyloid precursor proteins (hAPP) and amyloid-beta peptides (Abeta) in neurons develop phenotypic alterations resembling Alzheimer's disease (AD). The mechanisms underlying cognitive deficits in AD and hAPP mice are largely unknown. We have identified two molecular alterations that accurately reflect AD-related cognitive impairments. Learning deficits in mice expressing familial AD-mutant hAPP correlated strongly with decreased levels of the calcium-binding protein calbindin-D28k (CB) and the calcium-dependent immediate early gene product c-Fos in granule cells of the dentate gyrus, a brain region critically involved in learning and memory. These molecular alterations were age-dependent and correlated with the relative abundance of Abeta1-42 but not with the amount of Abeta deposited in amyloid plaques. CB reductions in the dentate gyrus primarily reflected a decrease in neuronal CB levels rather than a loss of CB-producing neurons. CB levels were also markedly reduced in granule cells of humans with AD, even though these neurons are relatively resistant to AD-related cell death. Thus, neuronal populations resisting cell death in AD and hAPP mice can still be drastically altered at the molecular level. The tight link between Abeta-induced cognitive deficits and neuronal depletion of CB and c-Fos suggests an involvement of calcium-dependent pathways in AD-related cognitive decline and could facilitate the preclinical evaluation of novel AD treatments.