Role of genes linked to sporadic Alzheimer’s disease risk in the production of β-amyloid peptides

Alzheimer’s disease (AD) is characterized by the presence of toxic protein aggregates or plaques composed of the amyloid β (Aβ) peptide. Various lengths of Aβ peptide are generated by proteolytic cleavages of the amyloid precursor protein (APP). Mutations in many familial AD-associated genes affect the production of the longer Aβ42 variant that preferentially accumulates in plaques. In the case of sporadic or late-onset AD, which accounts for greater than 95% of cases, several genes are implicated in increasing the risk, but whether they also cause the disease by altering amyloid levels is currently unknown. Through loss of function studies in a model cell line, here RNAi-mediated silencing of several late onset AD genes affected Aβ levels is shown. However, unlike the genes underlying familial AD, late onset AD-susceptibility genes do not specifically alter the Aβ42/40 ratios and suggest that these genes probably contribute to AD through distinct mechanisms.     

Cardiovascular risk factors and Alzheimer’s disease

Alzheimer’s disease is a devastating condition that is increasing in prevalence. No known prevention or cure exists for Alzheimer’s disease. Cardiovascular risk factors are prevalent and increase in the elderly, and there have been conflicting reports of associations between modifiable cardiovascular risk factors and Alzheimer’s disease. The mechanisms for these associations are uncertain, but they are likely to be the result of a combination of direct and cerebrovascular disease-related mechanisms. From this standpoint, diabetes and hyperinsulinemia seem to have the strongest evidence from laboratory, clinical, and epidemiologic studies. Studies have also indicated that hypertension, hyperlipidemia, hyperhomocysteinemia, and smoking are potentially important risk factors for Alzheimer’s disease.     

Evaluation of Styrylbenzene analog- FSB and its affinity to bind parenchymal plaques and tangles in patients of Alzheimer’s disease

Metabolic Brain Disease - Although several histochemical markers for senile plaques (SP) and neurofibrillary tangles (NFTs) have been synthesized since the discovery of plaques in Alzheimer’s...     

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

Through a comprehensive analysis of organellar markers in mouse models of Alzheimer’s disease, we document a massive accumulation of lysosome-like organelles at amyloid plaques and establish that the majority of these organelles reside within swollen axons that contact the amyloid deposits. This close spatial relationship between axonal lysosome accumulation and extracellular amyloid aggregates was observed from the earliest stages of β-amyloid deposition. Notably, we discovered that lysosomes that accumulate in such axons are lacking in multiple soluble luminal proteases and thus are predicted to be unable to efficiently degrade proteinaceous cargos. Of relevance to Alzheimer’s disease, β-secretase (BACE1), the protein that initiates amyloidogenic processing of the amyloid precursor protein and which is a substrate for these proteases, builds up at these sites. Furthermore, through a comparison between the axonal lysosome accumulations at amyloid plaques and neuronal lysosomes of the wild-type brain, we identified a similar, naturally occurring population of lysosome-like organelles in neuronal processes that is also defined by its low luminal protease content. In conjunction with emerging evidence that the lysosomal maturation of endosomes and autophagosomes is coupled to their retrograde transport, our results suggest that extracellular β-amyloid deposits cause a local impairment in the retrograde axonal transport of lysosome precursors, leading to their accumulation and a blockade in their further maturation. This study both advances understanding of Alzheimer’s disease brain pathology and provides new insights into the subcellular organization of neuronal lysosomes that may have broader relevance to other neurodegenerative diseases with a lysosomal component to their pathology.Alzheimer’s disease (AD) is the most common form of dementia associated with aging. Nonetheless, more than a century after the original definition of the disease, the identification of the fundamental cell biological processes that cause AD remains a major challenge. Major defining features of AD brain pathology, as elucidated by molecular and genetic studies in humans and mice, are as follows: the proteolytic processing of the amyloid precursor protein (APP) by the successive action of β- and γ-secretases to generate the toxic Aβ peptides, the accumulation of extracellular aggregates of Aβ, synapse dysfunction, and death of specific subpopulations of neurons (1–6). However, although mutations that result in enhanced APP expression and/or altered processing of APP into Aβ peptides drive the development of a subset of early onset familial forms of AD, the causes of the vastly more common late-onset AD are much less well understood.One major aspect of AD pathology that is observed in both humans and mouse models of the disease is the formation of amyloid plaques. These structures contain a core of aggregated extracellular Aβ that is surrounded by swollen, dystrophic neurites and microglial processes (7–13). Multiple studies in humans and mice have additionally reported an elevated abundance of putative lysosomes and/or lysosomal proteins around amyloid plaques (9–11, 14–16). These observations indicate an influence of extracellular β-amyloid deposits on the physiology of surrounding cells and raise questions about the underlying cell biological mechanisms and the contributions of such pathological changes to AD.The goal of this study was to investigate the cell biology of AD amyloid plaques to advance understanding of how the interactions between extracellular Aβ aggregates and surrounding brain tissues might contribute to disease pathology. Through studies of mouse models of AD, we found a robust relationship between extracellular Aβ aggregates and the massive accumulation of lysosomes (but not other organelles) within swollen axons adjacent to such aggregates. A striking new feature of the lysosomes that accumulate within these dystrophic axons is their relatively low levels of multiple lysosomal proteases. Because we also identified a subpopulation of lysosomes with similar properties in the distal neuronal compartments of normal brain tissue and primary neuron cultures, the distinct composition of the axonal lysosomes that accumulate at amyloid plaques most likely reflects a blockade in their retrograde transport and maturation. More broadly, our characterization of a distinct population of axonal lysosomes that is selectively accumulated at amyloid plaques provides a foundation for the future elucidation of the mechanisms that underlie their biogenesis, function, and contributions to neuronal physiology and pathology.     

Distinctive features of microsaccades in Alzheimer’s disease and in mild cognitive impairment

During visual fixation, the eyes are never completely still, but produce small involuntary movements, called “fixational eye movements,” including microsaccades, drift, and tremor. In certain neurological disorders, attempted fixation results in abnormal fixational eye movements with distinctive characteristics. Thus, determining how normal fixation differs from pathological fixation has the potential to aid early and differential noninvasive diagnosis of neurological disease as well as the quantification of its progression and response to treatment. Here, we recorded the eye movements produced by patients with Alzheimer’s disease, patients with mild cognitive impairment, and healthy age-matched individuals during attempted fixation. We found that microsaccade magnitudes, velocities, durations, and intersaccadic intervals were comparable in the three subject groups, but microsaccade direction differed in patients versus healthy subjects. Our results indicate that microsaccades are more prevalently oblique in patients with Alzheimer’s disease or mild cognitive impairment than in healthy subjects. These findings extended to those microsaccades paired in square-wave jerks, supporting the hypothesis that microsaccades and square-wave jerks form a continuum, both in healthy subjects and in neurological patients.

Electronic supplementary material

The online version of this article (doi:10.1007/s11357-013-9582-3) contains supplementary material, which is available to authorized users.     

Blockade of EphA4 signaling ameliorates hippocampal synaptic dysfunctions in mouse models of Alzheimer’s disease

Alzheimer’s disease (AD), characterized by cognitive decline, has emerged as a disease of synaptic failure. The present study reveals an unanticipated role of erythropoietin-producing hepatocellular A4 (EphA4) in mediating hippocampal synaptic dysfunctions in AD and demonstrates that blockade of the ligand-binding domain of EphA4 reverses synaptic impairment in AD mouse models. Enhanced EphA4 signaling was observed in the hippocampus of amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model of AD, whereas soluble amyloid-β oligomers (Aβ), which contribute to synaptic loss in AD, induced EphA4 activation in rat hippocampal slices. EphA4 depletion in the CA1 region or interference with EphA4 function reversed the suppression of hippocampal long-term potentiation in APP/PS1 transgenic mice, suggesting that the postsynaptic EphA4 is responsible for mediating synaptic plasticity impairment in AD. Importantly, we identified a small-molecule rhynchophylline as a novel EphA4 inhibitor based on molecular docking studies. Rhynchophylline effectively blocked the EphA4-dependent signaling in hippocampal neurons, and oral administration of rhynchophylline reduced the EphA4 activity effectively in the hippocampus of APP/PS1 transgenic mice. More importantly, rhynchophylline administration restored the impaired long-term potentiation in transgenic mouse models of AD. These findings reveal a previously unidentified role of EphA4 in mediating AD-associated synaptic dysfunctions, suggesting that it is a new therapeutic target for this disease.Cognitive impairment, regarded as an early manifestation of Alzheimer’s disease (AD), is attributable to disruptions of synaptic functions which correlate with the severity of memory deficit in AD (1). Soluble amyloid-β peptide oligomers (Aβ), which are generated by the proteolytic cleavage of amyloid precursor protein (APP), are believed to be a major causative agent of synaptic impairment during AD progression (2). Thus, reversing Aβ-induced synaptic deficits is considered a promising therapeutic approach for alleviating cognitive impairment in AD (3).Aβ binds to synaptic sites (4), resulting in synaptic loss and reduced glutamatergic synaptic transmission (5, 6). Aβ also rapidly impairs synaptic plasticity in the hippocampus; this includes the inhibition of long-term potentiation (LTP) (2) and facilitation of long-term depression (LTD) (7), which are major cellular mechanisms associated with learning and memory. Synaptic defects triggered by Aβ are mediated by the internalization and down-regulation of both NMDA- and AMPA-type glutamate receptors (8, 9) together with a reduction of dendritic spines (6), where excitatory synapses are located. Therefore, identifying molecular targets that mediate the action of Aβ in synaptic depression in AD is crucial for the development of therapeutic interventions for AD. Interestingly, various cell surface receptors such as α7-nicotinic acetylcholine receptors, metabotropic glutamate receptors, insulin receptors, and the receptor tyrosine kinase, EphB2, are reported to mediate the action of Aβ at synapses (10).The erythropoietin-producing hepatocellular (Eph) family of receptor tyrosine kinases is important for the regulation of synapse development and synaptic plasticity (11, 12). EphB enhances synapse development via its interaction with NMDA receptors (13), whereas EphA4, which is mainly expressed in the adult hippocampus, acts as a negative regulator of neurotransmission and hippocampal synaptic plasticity (14). EphA4 activation by its ligands, ephrins, triggers forward signaling (12) that leads to the retraction of dendritic spines via cyclin-dependent kinase 5 (Cdk5)-dependent RhoA activation and reduced cell adhesion (15–17). EphA4 also causes the removal of synaptic and surface AMPA receptors during homeostatic plasticity (18, 19). Interestingly, AD patients with only mild cognitive deficits exhibit deregulated EphB and EphA4 expression (20). Given that EphA4 activation results in dendritic spine loss and reduced AMPA receptor abundance (14, 19, 21), which are potential mechanisms that underlie synaptic dysfunctions in AD (6, 8), we investigated the possible link between EphA4 signaling and Aβ-induced synaptic failure.The present study demonstrates that EphA4 mediates the Aβ-induced impairment of synaptic plasticity. Depletion of postsynaptic EphA4 or blockade of the activity of EphA4 through targeting its ligand-binding domain reversed the synaptic deficits in AD mouse models. Importantly, molecular docking analysis identified a small molecule, rhynchophylline (Rhy), as a candidate EphA4 inhibitor. Rhy rescued the impaired neurotransmission induced by Aβ as well as the LTP defects in the AD mouse models. Thus, the present findings not only reveal an important role of EphA4 in the pathogenesis of AD, but also identify a small-molecule inhibitor of EphA4 that can be further developed as a potential therapeutic intervention for AD.     

Microglial autophagy is impaired by prolonged exposure to β-amyloid peptides: evidence from experimental models and Alzheimer’s disease patients

GeroScience - Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the presence of misfolded proteins, amyloid-β (Aβ) aggregates, and...     

Genetic heterogeneity of Alzheimer’s disease in subjects with and without hypertension

GeroScience - Alzheimer’s disease (AD) is a progressive neurodegenerative disorder caused by the interplay of multiple genetic and non-genetic factors. Hypertension is one of the AD risk...     

Anti-amyloidogenic,anti-oxidant and anti-apoptotic role of gelsolin in Alzheimer’s disease

Fibrillar amyloid beta-protein (Aβ) is a major component of amyloid plaques in the brains of individuals with Alzheimer’s disease (AD) and of adults with Down syndrome (DS). Gelsolin, a cytoskeletal protein, is present both intracellularly (cytoplasmic form) and extracellularly (secretory form in biological fluids). These two forms of gelsolin differ from each other in length and in cysteinyl thiol groups. Previous studies from our and other groups have identified the anti-amyloidogenic role of gelsolin in AD. Our studies showed that both plasma and cytosolic gelsolin bind to Aβ, and that gelsolin inhibits the fibrillization of Aβ and solubilizes preformed fibrils of Aβ. Other studies have shown that peripheral administration of plasma gelsolin or transgene expression of plasma gelsolin can reduce amyloid load in the transgenic mouse model of AD. Our recent studies showed that gelsolin expression increases in cells in response to oxidative stress. Oxidative damage is considered a major feature in the pathophysiology of AD. Aβ not only can induce oxidative stress, but also its generation is increased as a result of oxidative stress. In this article, we review evidence of gelsolin as an anti-amyloidogenic agent that can reduce amyloid load by acting as an inhibitor of Aβ fibrillization, and as an antioxidant and anti-apoptotic protein.     

Endosomal‐lysosomal dysfunctions in Alzheimer’s disease: Pathogenesis and therapeutic interventions

Metabolic Brain Disease - The endosomal-lysosomal system mediates the process of protein degradation through endocytic pathway. This system consists of early endosomes, late endosomes, recycling...     

Connection between sleeping patterns and cognitive deterioration in women with Alzheimer’s disease

Sleep and Breathing - Alzheimer’s disease (AD) causes symptoms such as dementia, memory loss, disorientation, and even aggressiveness, and is more common in women than in men. AD may also...     

Urolithin A reduces amyloid-beta load and improves cognitive deficits uncorrelated with plaque burden in a mouse model of Alzheimer’s disease

GeroScience - In the present study, we investigated the effects of urolithin A (UA), a metabolite generated from ellagic acid via its metabolism by gut bacteria, as an autophagy activator with...     

Actions and interactions of the IGF system in Alzheimer’s disease: review and hypotheses

Insulin-like growth factors (IGF) are pleiotrophic polypeptides affecting all aspects of growth and development. The IGF system, including ligands, receptors, binding proteins and proteases is also involved in pathophysiological conditions, such as cancer and degenerative conditions. In this review, the actions and interactions of the IGF system as it relates to Alzheimer’s disease will be investigated.     

p75 reduces β-amyloid-induced sympathetic innervation deficits in an Alzheimer's disease mouse model

β-Amyloid (Aβ) has adverse effects on brain cells, but little is known about its effects on the peripheral nervous system in Alzheimer''s disease (AD). Several lines of in vitro evidence suggest that the neurotrophin receptor p75 mediates or exacerbates Aβ-induced neurotoxicity. Here, we show that p75-deficient sympathetic neurons are more sensitive to Aβ-induced neurite growth inhibition. To investigate the role of p75 in the sympathetic nervous system of AD, p75 mutant mice were crossed with a mouse line of AD model. The majority of p75-deficient AD mice died by 3 weeks of age. The lethality is associated with severe defects in sympathetic innervation to multiple organs. When 1 copy of the BACE1 gene encoding a protein essential in Aβ production was deleted in p75-deficient AD mice, sympathetic innervation was significantly restored. These results suggest that p75 is neuroprotective for the sympathetic nervous system in a mouse model of AD.Although Alzheimer''s disease (AD) is generally considered a neurodegenerative disease that primarily affects the brain because of the presence of intracellular neurofibrillary tangles and plaques within the neocortex and hippocampus (1), deficits in other nervous systems, including the sympathetic nervous system, are observed and may contribute to the pathogenesis and mortality of AD (2, 3). β-Amyloid (Aβ) peptide is the product of stepwise processing of the amyloid protein precursor and is the major component of the plaques in the brain of AD (3). A large body of studies has established that Aβ oligomers or aggregates are toxic to brain cells, yet little is known about their effects on neurons of the peripheral nervous system. Identifying genetic factors that modify the neurotoxicity of Aβ in both the brain and the peripheral nervous system will increase our understanding of the biology of AD and may provide insights into development of treatments centered on Aβ (4).The neurotrophin receptor p75 is a member of the TNF receptor superfamily. p75 has been shown to interact with different partners to mediate diverse functions, including cell survival, cell death, and axon guidance, depending on the partner with which it complexes (5–7). Several lines of evidence suggest that p75 plays a role in neurotoxicity associated with Aβ; however, the exact role of p75 remains controversial. Aβ has been shown to bind p75 (8–10) and activate downstream signaling pathways, such as JNK, NF-κB, and PI3K. Thus, p75 has been suggested to be a receptor for Aβ and mediate Aβ-induced neurotoxicity. Several studies suggest that overexpression of p75 in a variety of cell lines could confer sensitivity to Aβ-induced toxicity (9, 11, 12), whereas p75-deficient mouse hippocampal neurons are resistant to Aβ-induced toxicity (13). Aβ-induced cell death of PC12 cells requires JNK activation, and p75 plays a role in JNK activation (14, 15). In contrast, a neuroprotective role for p75 is suggested in human hippocampal neurons (16). It is not clear whether these disparate observations are due to experimental and physiological differences in different culture systems. Additionally, the discrepancy from in vitro experiments underscores the importance of studying the role of p75 in Aβ-induced neurotoxicity in vivo.Here, we show that p75-deficient sympathetic neurons are more sensitive to Aβ peptide-induced neurite growth inhibition in vitro. In addition, when p75 mutant mice are crossed with a mouse line of AD model, sympathetic innervation to multiple organs is severely compromised in p75-deficient AD mice. When p75-deficient AD mice are crossed with BACE1 mutant mice, sympathetic innervation is markedly restored. Our results suggest that p75 is neuroprotective for the sympathetic nervous system in an AD mouse model.     

Efficacy of language assessment in Alzheimer’s disease: comparing in-person examination and telemedicine

Background:

With the large number of aging individuals requiring screening of cognitive functions for dementing illnesses, there is a necessity for innovative evaluation approaches. One domain that should allow for online, at a distance, examination is speech and language dysfunction, if the auditory and visual transmission is of sufficient quality to allow adequate patient participation and reliable, valid interpretation of signs and symptoms (Duffy et al 1997).

Objective:

Examine the effectiveness of language assessment in mild Alzheimer’s patients using telemedicine (TM) compared with traditional in-person (IP) assessment.

Design:

Ten patients with mild Alzheimer’s disease, enrolled at a Geriatric Memory Clinic received a battery of standard language tests under two conditions: face-to-face and via satellite TM.

Results:

Comparison of TM and IP testing conditions were assessed within each for scores on each test in the two conditions. On each of the five language tasks, the Wilcoxon signed ranks test indicated no significant difference on performance between the TM and IP conditions for each participant. Overall acceptance of the TM evaluation in an elderly population was rated at a high level except for one individual.

Conclusion:

Telemedicine can improve access to speech and language evaluation services which is relevant to both dementia and other neurological diseases of the elderly. In particular, this specific assessment tool can be used to provide evaluations in under-served rural areas.     

Co-localization of hyperphosphorylated tau and caspases in the brainstem of Alzheimer’s disease patients

Hyperphosphorylation of microtubule associated protein tau had limited studies in Alzheimer’s disease (AD) brainstem. We compared the distribution and number of neurons with hyperphosphorylated tau in two age groups of AD brainstems with mean ages of 65.4 ± 5.7 and 91.1 ± 6.4 years. The degree of co-localization of hyperphosphorylated tau positive cells with either cleaved caspase-3 or cleaved caspase-6 was also quantified. Results showed hyperphosphorylated tau mainly occurred in hypoglossal, dorsal motor vagal, trigeminal sensory/motor nuclei as well as in dorsal raphe, locus coeruleus and substantia nigra. Older AD brainstem consistently had higher density of hyperphosphorylated tau cells. Up to 70% of tau positive cells also displayed either cleaved caspase-3 or caspase-6, and the number of co-localized tau cells in each caspase subfamily group was always higher in older aged group. Some hyperphosphorylated tau cells with cleaved caspases had TUNEL positive nuclei. These findings suggest that these latter cells went through the apoptotic process or DNA fragmentation.     

Apolipoprotein E (APOE) genotype has dissociable effects on memory and attentional–executive network function in Alzheimer’s disease

The ε4 allele of the apolipoprotein E (APOE) gene is the major genetic risk factor for Alzheimer’s disease (AD), but limited work has suggested that APOE genotype may modulate disease phenotype. Carriers of the ε4 allele have been reported to have greater medial temporal lobe (MTL) pathology and poorer memory than noncarriers. Less attention has focused on whether there are domains of cognition and neuroanatomical regions more affected in noncarriers. Further, a major potential confound of prior in vivo studies is the possibility of different rates of clinical misdiagnosis for carriers vs. noncarriers. We compared phenotypic differences in cognition and topography of regional cortical atrophy of ε4 carriers (n = 67) vs. noncarriers (n = 24) with mild AD from the Alzheimer’s Disease Neuroimaging Initiative, restricted to those with a cerebrospinal fluid (CSF) molecular profile consistent with AD. Between-group comparisons were made for psychometric tests and morphometric measures of cortical thickness and hippocampal volume. Carriers displayed significantly greater impairment on measures of memory retention, whereas noncarriers were more impaired on tests of working memory, executive control, and lexical access. Consistent with this cognitive dissociation, carriers exhibited greater MTL atrophy, whereas noncarriers had greater frontoparietal atrophy. Performance deficits in particular cognitive domains were associated with disproportionate regional brain atrophy within nodes of cortical networks thought to subserve these cognitive processes. These convergent cognitive and neuroanatomic findings in individuals with a CSF molecular profile consistent with AD support the hypothesis that APOE genotype modulates the clinical phenotype of AD through influence on specific large-scale brain networks.