Early Memory Loss Research Articles

Genetically-controlled Vesicle-Associated Membrane Protein 1 expression may contribute to Alzheimer’s pathophysiology and susceptibility

BackgroundAlzheimer’s disease is a neurodegenerative disorder in which extracellular deposition of β-amyloid (Aβ) oligomers causes synaptic injury resulting in early memory loss, altered homeostasis, accumulation of hyperphosphorylated tau and cell death. Since proteins in the SNAP (Soluble N-ethylmaleimide-sensitive factor Attachment Protein) REceptors (SNARE) complex are essential for neuronal Aβ release at pre-synaptic terminals, we hypothesized that genetically controlled SNARE expression could alter neuronal Aß release at the synapse and hence play an early role in Alzheimer’s pathophysiology.ResultsHere we report 5 polymorphisms in Vesicle-Associated Membrane Protein 1 (VAMP1), a gene encoding a member of the SNARE complex, associated with bidirectionally altered cerebellar VAMP1 transcript levels (all p < 0.05). At the functional level, we demonstrated that control of VAMP1 expression by heterogeneous knockdown in mice resulted in up to 74% reduction in neuronal Aβ exocytosis (p < 0.001). We performed a case-control association study of the 5 VAMP1 expression regulating polymorphisms in 4,667 Alzheimer’s disease patients and 6,175 controls to determine their contribution to Alzheimer’s disease risk. We found that polymorphisms associated with increased brain VAMP1 transcript levels conferred higher risk for Alzheimer’s disease than those associated with lower VAMP1 transcript levels (p = 0.03). Moreover, we also report a modest protective association for a common VAMP1 polymorphism with Alzheimer’s disease risk (OR = 0.88, p = 0.03). This polymorphism was associated with decreased VAMP1 transcript levels (p = 0.02) and was functionally active in a dual luciferase reporter gene assay (p < 0.01).ConclusionsGenetically regulated VAMP1 expression in the brain may modify both Alzheimer’s disease risk and may contribute to Alzheimer’s pathophysiology.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-015-0015-x) contains supplementary material, which is available to authorized users.

Reducing hippocampal extracellular matrix reverses early memory deficits in a mouse model of Alzheimer's disease.

Alzheimer’s disease is caused by increased production or reduced clearance of amyloid-β, which results in the formation amyloid-β plaques and triggers a cascade of downstream events leading to progressive neurodegeneration. The earliest clinical symptoms of Alzheimer’s disease, i.e., memory loss, are however poorly understood from a molecular and cellular perspective. Here we used APPswe/PS1dE9 (APP/PS1) transgenic mice to study the early pre-pathological effects of increased amyloid-β levels on hippocampal synaptic plasticity and memory. Using an unbiased proteomics approach we show that the early increase in amyloid-β levels in APP/PS1 mice at three months of age coincides with a robust and significant upregulation of several protein components of the extracellular matrix in hippocampal synaptosome preparations. This increase in extracellular matrix levels occurred well before the onset of plaque formation and was paralleled by impairments in hippocampal long-term potentiation and contextual memory. Direct injection into the hippocampus of the extracellular matrix inactivating enzyme chondroitinase ABC restored both long-term potentiation and contextual memory performance. These findings indicate an important role for the extracellular matrix in causing early memory loss in Alzheimer’s disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-014-0076-z) contains supplementary material, which is available to authorized users.

Selective alterations of neurons and circuits related to early memory loss in Alzheimer's disease.

A progressive loss of episodic memory is a well-known clinical symptom that characterizes Alzheimer’s disease (AD). The beginning of this loss of memory has been associated with the very early, pathological accumulation of tau and neuronal degeneration observed in the entorhinal cortex (EC). Tau-related pathology is thought to then spread progressively to the hippocampal formation and other brain areas as the disease progresses. The major cortical afferent source of the hippocampus and dentate gyrus is the EC through the perforant pathway. At least two main circuits participate in the connection between EC and the hippocampus; one originating in layer II and the other in layer III of the EC giving rise to the classical trisynaptic (ECII → dentate gyrus → CA3 → CA1) and monosynaptic (ECIII → CA1) circuits. Thus, the study of the early pathological changes in these circuits is of great interest. In this review, we will discuss mainly the alterations of the granule cell neurons of the dentate gyrus and the atrophy of CA1 pyramidal neurons that occur in AD in relation to the possible differential alterations of these two main circuits.

Crtc1 activates a transcriptional program deregulated at early Alzheimer's disease-related stages.

Cognitive decline is associated with gene expression changes in the brain, but the transcriptional mechanisms underlying memory impairments in cognitive disorders, such as Alzheimer's disease (AD), are largely unknown. Here, we aimed to elucidate relevant mechanisms responsible for transcriptional changes underlying early memory loss in AD by examining pathological, behavioral, and transcriptomic changes in control and mutant β-amyloid precursor protein (APPSw,Ind) transgenic mice during aging. Genome-wide transcriptome analysis using mouse microarrays revealed deregulation of a gene network related with neurotransmission, synaptic plasticity, and learning/memory in the hippocampus of APPSw,Ind mice after spatial memory training. Specifically, APPSw,Ind mice show changes on a cAMP-responsive element binding protein (CREB)-regulated transcriptional program dependent on the CREB-regulated transcription coactivator-1 (Crtc1). Interestingly, synaptic activity and spatial memory induces Crtc1 dephosphorylation (Ser151), nuclear translocation, and Crtc1-dependent transcription in the hippocampus, and these events are impaired in APPSw,Ind mice at early pathological and cognitive decline stages. CRTC1-dependent genes and CRTC1 levels are reduced in human hippocampus at intermediate Braak III/IV pathological stages. Importantly, adeno-associated viral-mediated Crtc1 overexpression in the hippocampus efficiently reverses Aβ-induced spatial learning and memory deficits by restoring a specific subset of Crtc1 target genes. Our results reveal a critical role of Crtc1-dependent transcription on spatial memory formation and provide the first evidence that targeting brain transcriptome reverses memory loss in AD.

Clinical and molecular studies reveal a PSEN1 mutation (L153V) in a Peruvian family with early-onset Alzheimer's disease

Presenilin 1 (PSEN1) gene mutations are found in 30–70% of familial early-onset Alzheimer disease (EOAD) cases (onset <60 years). Prevalence of these mutations is highly variable including ethnic differences worldwide. No Peruvian kindred with familial AD (FAD) have been described. Standardized clinical evaluation and cognitive assessment were completed in a Peruvian family with severe EOAD. Clinical course was characterized by very early onset (before age 35 years), progressive cognitive impairment with early memory loss, spatial disorientation and executive dysfunction. We sequenced all exons of PSEN1 in the proband and identified a c.475C>G DNA change resulting in a p.L153V missense mutation in the transmembrane domain 2 of the gene. This mutation is also present in the three additional affected siblings but not in a non-affected family member consistent with segregation of this mutation with the disease. This is the first report of a Peruvian family affected with EOAD associated with a PSEN1 mutation. This same mutation has been reported previously in English and French families, but a novel variants very close to the mutation and ancestry informative markers analysis suggests the mutation might be of Amerindian or African origin in this Peruvian family.

Can a Memory Club Help Maintain Cognitive Function? A Pilot Investigation

In a pilot investigation we evaluated the impact of a structured early memory loss (EML) program intervention in a longitudinal (repeated measures) study of 55 persons with mild cognitive impairment or mild dementia. At four test sites we examined whether participation in the club—which sought to stimulate mental activity and social interaction, provide opportunities for light exercise, and teach memory strategies—would be associated with changes in cognitive function during 1 year. Controlling for relevant covariates, we found that club participation was associated with improvements in two of three executive function measures and maintenance of function in two of three memory measures. We observed decline, over time, on a measure of delayed recall. There were interactions between change and test site, indicating that some effects were related to where clubs were located. This pilot study suggests that EML clubs may be an efficacious, nonpharmacologic intervention for people with early memory loss. However, further research (especially randomized control trials) is needed before recommending widespread implementation of this program.

Reducing hippocampal extracellular matrix reverses early memory deficits in a mouse model of Alzheimer¿s disease

Alzheimer’s disease is caused by increased production or reduced clearance of amyloid-β, which results in the formation amyloid-β plaques and triggers a cascade of downstream events leading to progressive neurodegeneration. The earliest clinical symptoms of Alzheimer’s disease, i.e., memory loss, are however poorly understood from a molecular and cellular perspective. Here we used APPswe/PS1dE9 (APP/PS1) transgenic mice to study the early pre-pathological effects of increased amyloid-β levels on hippocampal synaptic plasticity and memory. Using an unbiased proteomics approach we show that the early increase in amyloid-β levels in APP/PS1 mice at three months of age coincides with a robust and significant upregulation of several protein components of the extracellular matrix in hippocampal synaptosome preparations. This increase in extracellular matrix levels occurred well before the onset of plaque formation and was paralleled by impairments in hippocampal long-term potentiation and contextual memory. Direct injection into the hippocampus of the extracellular matrix inactivating enzyme chondroitinase ABC restored both long-term potentiation and contextual memory performance. These findings indicate an important role for the extracellular matrix in causing early memory loss in Alzheimer’s disease.

Semantic Memory Functional MRI and Cognitive Function after Exercise Intervention in Mild Cognitive Impairment

Mild cognitive impairment (MCI) is associated with early memory loss, Alzheimer's disease (AD) neuropathology, inefficient or ineffective neural processing, and increased risk for AD. Unfortunately, treatments aimed at improving clinical symptoms or markers of brain function generally have been of limited value. Physical exercise is often recommended for people diagnosed with MCI, primarily because of its widely reported cognitive benefits in healthy older adults. However, it is unknown if exercise actually benefits brain function during memory retrieval in MCI. Here, we examined the effects of exercise training on semantic memory activation during functional magnetic resonance imaging (fMRI). Seventeen MCI participants and 18 cognitively intact controls, similar in sex, age, education, genetic risk, and medication use, volunteered for a 12-week exercise intervention consisting of supervised treadmill walking at a moderate intensity. Both MCI and control participants significantly increased their cardiorespiratory fitness by approximately 10% on a treadmill exercise test. Before and after the exercise intervention, participants completed an fMRI famous name discrimination task and a neuropsychological battery, Performance on Trial 1 of a list-learning task significantly improved in the MCI participants. Eleven brain regions activated during the semantic memory task showed a significant decrease in activation intensity following the intervention that was similar between groups (p-values ranged 0.048 to 0.0001). These findings suggest exercise may improve neural efficiency during semantic memory retrieval in MCI and cognitively intact older adults, and may lead to improvement in cognitive function. Clinical trials are needed to determine if exercise is effective to delay conversion to AD.

Enhancing Cognitive Fitness in Adults: A Guide to the Use and Development of Community-Based Programsedited by Hartman-SteinPaula E. and LaRueAsenath; New York, Springer Publishing, 2011, 522 pages, $169

Back to table of contents Previous article Next article Book ReviewsFull AccessEnhancing Cognitive Fitness in Adults: A Guide to the Use and Development of Community-Based ProgramsJeffrey L. Geller, M.D., M.P.H., , and Jacqueline Kerr, Ph.D.Jeffrey L. GellerSearch for more papers by this author, M.D., M.P.H., Editor, and Jacqueline KerrSearch for more papers by this author, Ph.D.Published Online:1 Oct 2012https://doi.org/10.1176/appi.ps.631004AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail edited by Hartman-SteinPaula E. and LaRueAsenath; New York, Springer Publishing, 2011, 522 pages, $169When I was asked to review this book, I had also received a request as director of a Successful Aging program to review the current research on “brain fitness” and present it to my program participants. My main area of research is physical activity of older adults, and in the past I have reviewed the literature on cognitive functioning and exercise. But I am a novice when it comes to other programs related to cognitive wellness. Thus my metric for judging the book was, could I read it (in my few spare moments before bedtime) and formulate a practical presentation for older adults in a retirement community?Given that I just delivered said presentation, my resounding answer is yes. Not only was the book easy to read (literally I read most of it as bedside reading), the information was extremely practical and enlightening. Admittedly, I followed up on many of the programs with online searches, but the book was a fantastic starting point.I felt engaged from the start as the editors shared personal stories of cognitive challenges in their families. The scope of the book was appropriate, covering multiple types of programs and always stating how much research had been conducted. Theoretical constructs, such as skill transfer, were clearly outlined, and practical tips for judging consumer brain fitness programs were provided. I learned about basic memory enhancement techniques, about aids that we should use because our memories can fail us at any age, and about activities that lead to social engagement and cognitive sweat. In particular, the chapter that described the Odyssey of the Mind program was helpful because it demonstrated how complex problem solving and the presentation of solutions involve multiple domains of thinking, memory, and reasoning.Practitioners will find this book useful because they can learn some simple tips to help aging patients who do or do not have memory problems. They will be able to recommend types of activities that a patient could try informally (playing improvisation games, for example) or through existing programs if they are available locally (such as Experience Corps and Early Memory Loss Clubs). Or if they desired, they could try to deliver a program in their practice. Many of the chapters include guidelines on how to set up and run sessions.One chapter suggests checking the National Institutes of Health Web site (consensus.nih.gov) for consensus statements on research conducted to date, which I did, and I concluded that the book echoes current understanding and future directions.Dr. Kerr is with the Department of Family and Preventive Medicine, University of California, San Diego.The reviewer reports no competing interests. FiguresReferencesCited byDetailsCited byNone Volume 63Issue 10 October 2012Pages e5-e5 Metrics The reviewer reports no competing interests.PDF download History Published online 1 October 2012 Published in print 1 October 2012

The role of leisure within the dementia context

While our understanding of the subjective experience of dementia is growing, leisure's role within that experience is less clear. This study, guided by hermeneutic phenomenology, aimed to understand the meaning and experience of leisure for persons living with early stage memory loss. Four participants with early stage dementia participated in interviews, participant observation, and photovoice, in which participants are given cameras and asked to take photos of their day to day lives (Wang, 1999). Data revealed that participants experienced daily life with dementia, including leisure, within a paradox of challenge and hope. They struggled with the changes they experienced as a result of dementia, such as muddled thinking, fluctuating abilities, draining energy, frightening awareness, and disquieting emotions. However, they found ways to tackle life with dementia, by reconciling life as it is, battling through by being proactive, living through relationships, being optimistic, and prolonging engagement in meaningful activity to live their lives with hope.

Clinical and Molecular Studies Reveal a PSEN1 Mutation (L153V) in a Peruvian Family with Early-Onset Alzheimer's Disease (P05.072)

Objective: To describe the clinical and molecular characteristics of an early onset Alzheimer9s disease Peruvian family. Background Early onset forms of Alzheimer9s disease are associated with genetic causes. Presenilin 1 (PSEN1) gene mutations are found in 30 to 70% of familial cases with onset before age of 55 years. Prevalence of these mutations is highly variable including ethnic differences worldwide. No Peruvian kindred with FAD has been described. Design/Methods: Four siblings of a mestizo Peruvian family, were evaluated and followed at Instituto Nacional de Ciencias Neurologicas for the past two years. Informed consent was obtained for genetic analysis in all participants. Standardized clinical evaluation and cognitive assessment was completed in proband and three affected siblings. We sequenced all exons and bordering intron regions or the PSEN1 gene in the proband and three affected siblings. Results: All four siblings developed a progressive very early onset Alzheimer9s dementia. Father was also affected and died at age of 60. The clinical course was characterized by early onset (before age 35), progressive cognitive impairment with early memory loss, spatial disorientation and executive dysfunction. The oldest sibling is fully dependent and confined to a wheelchair after five years of symptoms. Genetic analysis revealed the p.L153V (c.457C>G) mutation in the transmembrane domain of PSEN1 in all four living affected siblings. Conclusions: This is the first report of a Peruvian family affected with very early onset dementia associated with a PSEN1 mutation. This same mutation has been reported twice previously in English and French families. Haplotype analysis and comparisons with appropriate control populations (Spanish, Peruvian Native) will allow us to determine the likelihood this mutation has occurred on a Native American genetic background. Disclosure: Dr. Cornejo has received personal compensation for activities with Schwarz Biosciences. Dr. Cornejo has received research support from the International Clinical Research Fellows Program at Vanderbilt University Dr. Leverenz has received personal compensation for activities with Bayer Pharmaceuticals and Teva as a consultant. Dr. Lindo-Samanamud has nothing to disclose. Dr. Mata has nothing to disclose. Dr. Mazzetti has received personal compensation for activities with Novartis, Schwarz Biosciences, and Eli Lilly. Dr. Meza-Vega has nothing to disclose. Dr. Yu has nothing to disclose. Dr. Bird has received personal compensation for activities with Athena Diagnostics for speakers bureau and licensing fees.Dr. Bird has received liscensing payments from Athena Diagnostics.

StoryCorps’ Memory Loss Initiative: Enhancing personhood for storytellers with memory loss

StoryCorps’ Memory Loss Initiative was designed to gather oral histories of people with memory loss. This study investigated the StoryCorps interview experience for storytellers who self identify with early stage memory loss and the persons who interviewed them. StoryCorps interviews took place in Milwaukee, Chicago, and New York. Follow-up interviews were conducted with 42 persons with memory loss, along with 27 family members who participated in the StoryCorps interviews. Results revealed that the StoryCorps experience was a meaningful activity that allowed participants to acknowledge the beauty of the present moment, to reflect and engage in meaningful conversations, to re-affirm both the selfhood of individuals with memory loss and their relationships with family members, and to and be a part of national history while leaving a legacy for future generations within families. The findings are discussed within the context of personhood enhancing strategies for persons with memory loss.

Primary Cerebral Blood Flow Deficiency and Alzheimer's Disease: Shadows and Lights

Alzheimer's disease (AD) is a degenerative disorder characterized by a decreased regional cerebral blood flow (CBF). It is most likely that a reduction in CBF could displace a pathway leading to AD genesis, in so far neuron death explains a sustained reduction in the supply of oxygen, glucose, and nutrients. Nevertheless, the concept of secondary CBF deficiency cannot explain the critical stages of early memory loss while, on the other hand, the picture of progressive ischemia due to primary CBF decline sheds light on the course of AD in a most persuasive manner. The concept of primary CBF deficiency is even more strengthened by the lack of correlation between degree of dementia and amount of CBF. Vascular abnormalities, frequently observed to co-occur with AD, might play a critical role in the initiation and aggravation of AD pathology given that the elimination of amyloid-β (Aβ) through a vascular route is an important brain Aβ clearance mechanism and its failure leads to formation of vascular amyloidosis and dense-core plaques. The goal of this review is to provide scientists comprehensive knowledge of the state-of the art influence vascular damage and reduced perfusion have on the final development of AD and to hopefully stimulate more research in this area of neuroscience.

Activation of D1/D5 Dopamine Receptors Protects Neurons from Synapse Dysfunction Induced by Amyloid-β Oligomers

Soluble oligomers of the amyloid-β peptide (AβOs) accumulate in the brains of Alzheimer disease (AD) patients and are implicated in synapse failure and early memory loss in AD. AβOs have been shown to impact synapse function by inhibiting long term potentiation, facilitating the induction of long term depression and inducing internalization of both AMPA and NMDA glutamate receptors, critical players in plasticity mechanisms. Because activation of dopamine D1/D5 receptors plays important roles in memory circuits by increasing the insertion of AMPA and NMDA receptors at synapses, we hypothesized that selective activation of D1/D5 receptors could protect synapses from the deleterious action of AβOs. We show that SKF81297, a selective D1/D5 receptor agonist, prevented the reduction in surface levels of AMPA and NMDA receptors induced by AβOs in hippocampal neurons in culture. Protection by SKF81297 was abrogated by the specific D1/D5 antagonist, SCH23390. Levels of AMPA receptor subunit GluR1 phosphorylated at Ser(845), which regulates AMPA receptor association with the plasma membrane, were reduced in a calcineurin-dependent manner in the presence of AβOs, and treatment with SKF81297 prevented this reduction. Establishing the functional relevance of these findings, SKF81297 blocked the impairment of long term potentiation induced by AβOs in hippocampal slices. Results suggest that D1/D5 receptors may be relevant targets for development of novel pharmacological approaches to prevent synapse failure in AD.

Do older adults with early memory loss wish to be told if subsequently diagnosed with Alzheimer’s disease?

Do older adults with early memory loss wish to be told if subsequently diagnosed with Alzheimer’s disease?

P3-173: Apolipoprotein E frequency in posterior cortical atrophy and typical Alzheimer’s disease

Typical Alzheimer's disease (AD) is characterized by early episodic memory loss, whereas Posterior Cortical Atrophy (PCA) is characterized by visual agnosias, with a relative sparing of episodic memory early in the disease course. The majority of cases of PCA share pathological features with those of typical AD. A well defined risk factor of typical AD is the presence of the apolipoprotein E (APOE) 4 allele. To compare the APOE 4 allele frequency in typical AD and PCA. We conducted a case control study in which the APOE status was determined on 22 patients who fulfilled clinical criteria for PCA, were longitudinally assessed in our Alzheimer's Disease Research Centre and had stored DNA. These patients were matched for age at onset and sex to 37 cases of typical AD diagnosed by the NINCDS–ADRDA criteria, and 38 controls. The APOE4 allele frequency was compared using a chi–square test. Furthermore, the PCA cases were stratified by age at onset > 60 to access for possible interaction. There was no difference in years of education, or disease severity based on the MMSE, between the cases with PCA and typical AD. The mean age at onset was 60 years in both groups. The APOE4 allele frequency was 29.5% for PCA, 47.0% for typical AD, and 7.9% for controls. There was no difference in APOE 4 allele frequency between the cases of PCA and typical AD (p=0.47), or between PCA and controls (p=0.12). However, there was a difference between typical AD cases and normal controls (p =0.004). There was no difference when the PCA cases were stratified by age at onset > 60. We did not find any evidence for a difference in the APOE 4 allele frequency between PCA and typical AD.

Neuropsychological Differences Between Frontotemporal Dementia and Alzheimer's Disease: A Review

This paper surveys the similarities and differences between frontotemporal dementia (FTD) and Alzheimer's disease (AD). The review covers findings primarily from neuropsychological studies on memory, language, attention/executive function, and visuospatial abilities. However, neuropsychiatric and neuroimaging data are also briefly discussed. Distinguishing features of both FTD and AD are described in order to present a comprehensive clinical picture of these dementing diseases, which is essential for the process of differential diagnosis. The cause of specific cognitive deficits is also considered. Our comprehensive review of the empirical literature reveals that AD is characterized by early memory loss and visuospatial problems, while among the main features of FTD are behavioral abnormalities and executive dysfunctions.

Synaptic Targeting by Alzheimer's-Related Amyloid β Oligomers

The cognitive hallmark of early Alzheimer's disease (AD) is an extraordinary inability to form new memories. For many years, this dementia was attributed to nerve-cell death induced by deposits of fibrillar amyloid beta (Abeta). A newer hypothesis has emerged, however, in which early memory loss is considered a synapse failure caused by soluble Abeta oligomers. Such oligomers rapidly block long-term potentiation, a classic experimental paradigm for synaptic plasticity, and they are strikingly elevated in AD brain tissue and transgenic-mouse AD models. The current work characterizes the manner in which Abeta oligomers attack neurons. Antibodies raised against synthetic oligomers applied to AD brain sections were found to give diffuse stain around neuronal cell bodies, suggestive of a dendritic pattern, whereas soluble brain extracts showed robust AD-dependent reactivity in dot immunoblots. Antigens in unfractionated AD extracts attached with specificity to cultured rat hippocampal neurons, binding within dendritic arbors at discrete puncta. Crude fractionation showed ligand size to be between 10 and 100 kDa. Synthetic Abeta oligomers of the same size gave identical punctate binding, which was highly selective for particular neurons. Image analysis by confocal double-label immunofluorescence established that >90% of the punctate oligomer binding sites colocalized with the synaptic marker PSD-95 (postsynaptic density protein 95). Synaptic binding was accompanied by ectopic induction of Arc, a synaptic immediate-early gene, the overexpression of which has been linked to dysfunctional learning. Results suggest the hypothesis that targeting and functional disruption of particular synapses by Abeta oligomers may provide a molecular basis for the specific loss of memory function in early AD.

Therapeutic effects of PKC activators in Alzheimer's disease transgenic mice.

Alzheimer's disease (AD) characteristically presents with early memory loss. Regulation of K(+) channels, calcium homeostasis, and protein kinase C (PKC) activation are molecular events that have been implicated during associative memory which are also altered or defective in AD. PKC is also involved in the processing of the amyloid precursor protein (APP), a central element in AD pathophysiology. In previous studies, we demonstrated that benzolactam (BL), a novel PKC activator, reversed K(+) channels defects and enhanced secretion of APP alpha in AD cells. In this study we present data showing that another PKC activator, bryostatin 1, at subnanomolar concentrations dramatically enhances the secretion of the alpha-secretase product sAPP alpha in fibroblasts from AD patients. We also show that BL significantly increased the amount of sAPP alpha and reduced A beta 40 in the brains of APP[V717I] transgenic mice. In a more recently developed AD double-transgenic mouse, bryostatin was effective in reducing both brain A beta 40 and A beta 42. In addition, bryostatin ameliorated the rate of premature death and improved behavioral outcomes. Collectively, these data corroborate PKC and its activation as a potentially important means of ameliorating AD pathophysiology and perhaps cognitive impairment, thus offering a promising target for drug development. Because bryostatin 1 is devoid of tumor-promoting activity and is undergoing numerous clinical studies for cancer treatment in humans, it might be readily tested in patients as a potential therapeutic agent for Alzheimer's disease.

Ionic conductance determinants of synaptic memory nets and their implications for Alzheimer's disease

Electrical and chemical signals representing macroscopic "perturbations" in brain networks engage large numbers of transient "microscopic" ionic channel fluctuations in producing long-lasting changes of conductance (and thus potential). Repeated electrical and chemical signals that occur during associative training of living organisms (from mollusc to mammal) can cause ionic conductance changes lasting from days to many weeks. If a stimulus pattern reoccurs with sufficient frequency, voltage-dependent K(+) conductances-responsible for both synaptic and intrinsic membrane currents-become progressively less probabilistic and more deterministic. In effect, more deterministic ion channel functions record in associative memory more deterministic (i.e., higher probability) events in the environment. This memory has been found to be stored within brain networks as ensembles of local dendritic ionic conductance changes distributed throughout brain regions such as the hippocampus and cerebellar cortex. Numerous other studies taken together support the hypothesis that distributed dendritic loci store associative memory, do not involve long-term potentiation, are also loci for Alzheimer's disease (AD) pathophysiology, and can contribute to, if not be responsible for, early memory loss in clinically manifest AD. J. Neurosci. Res. 58:24-32, 1999. Published 1999 Wiley-Liss, Inc.