The Response of Cerebral Cortex to Haemorrhagic Damage: Experimental Evidence from a Penetrating Injury Model

Understanding the response of the brain to haemorrhagic damage is important in haemorrhagic stroke and increasingly in the understanding the cerebral degeneration and dementia that follow head trauma and head-impact sports. In addition, there is growing evidence that haemorrhage from small cerebral vessels is important in the pathogenesis of age-related dementia (Alzheimer’s disease). In a penetration injury model of rat cerebral cortex, we have examined the neuropathology induced by a needlestick injury, with emphasis on features prominent in the ageing and dementing human brain, particularly plaque-like depositions and the expression of related proteins. Needlestick lesions were made in neo- and hippocampal cortex in Sprague Dawley rats aged 3–5 months. Brains were examined after 1–30 d survival, for haemorrhage, for the expression of hyperphosphorylated tau, Aβ, amyloid precursor protein (APP), for gliosis and for neuronal death. Temporal cortex from humans diagnosed with Alzheimer’s disease was examined with the same techniques. Needlestick injury induced long-lasting changes–haem deposition, cell death, plaque-like deposits and glial invasion–along the needle track. Around the track, the lesion induced more transient changes, particularly upregulation of Aβ, APP and hyperphosporylated tau in neurons and astrocytes. Reactions were similar in hippocampus and neocortex, except that neuronal death was more widespread in the hippocampus. In summary, experimental haemorrhagic injury to rat cerebral cortex induced both permanent and transient changes. The more permanent changes reproduced features of human senile plaques, including the formation of extracellular deposits in which haem and Aβ-related proteins co-localised, neuronal loss and gliosis. The transient changes, observed in tissue around the direct lesion, included the upregulation of Aβ, APP and hyperphosphorylated tau, not associated with cell death. The findings support the possibility that haemorrhagic damage to the brain can lead to plaque-like pathology.     

Functional Impairment of Microglia Coincides with Beta-Amyloid Deposition in Mice with Alzheimer-Like Pathology

Microglial cells closely interact with senile plaques in Alzheimer’s disease and acquire the morphological appearance of an activated phenotype. The significance of this microglial phenotype and the impact of microglia for disease progression have remained controversial. To uncover and characterize putative changes in the functionality of microglia during Alzheimer’s disease, we directly assessed microglial behavior in two mouse models of Alzheimer’s disease. Using in vivo two-photon microscopy and acute brain slice preparations, we found that important microglial functions - directed process motility and phagocytic activity - were strongly impaired in mice with Alzheimer’s disease-like pathology compared to age-matched non-transgenic animals. Notably, impairment of microglial function temporally and spatially correlated with Aβ plaque deposition, and phagocytic capacity of microglia could be restored by interventionally decreasing amyloid burden by Aβ vaccination. These data suggest that major microglial functions progressively decline in Alzheimer’s disease with the appearance of Aβ plaques, and that this functional impairment is reversible by lowering Aβ burden, e.g. by means of Aβ vaccination.     

Intravenous Delivery of Targeted Liposomes to Amyloid-β Pathology in APP/PSEN1 Transgenic Mice

Extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles constitute the major neuropathological hallmarks of Alzheimer’s disease (AD). It is now apparent that parenchymal Aβ plaque deposition precedes behavioral signs of disease by several years. The development of agents that can target these plaques may be useful as diagnostic or therapeutic tools. In this study, we synthesized an Aβ-targeted lipid conjugate, incorporated it in stealth liposomal nanoparticles and tested their ability to bind amyloid plaque deposits in an AD mouse model. The results show that the particles maintain binding profiles to synthetic Aβ aggregates comparable to the free ligand, and selectively bind Aβ plaque deposits in brain tissue sections of an AD mouse model (APP/PSEN1 transgenic mice) with high efficiency. When administered intravenously, these long circulating nanoparticles appear to cross the blood-brain barrier and bind to Aβ plaque deposits, labeling parenchymal amyloid deposits and vascular amyloid characteristic of cerebral amyloid angiopathy.     

The Anti-Diabetic Drug Metformin Reduces BACE1 Protein Level by Interfering with the MID1 Complex

Alzheimer’s disease (AD), the most common form of dementia in the elderly, is characterized by two neuropathological hallmarks: senile plaques, which are composed of Aβ peptides, and neurofibrillary tangles, which are composed of hyperphosphorylated TAU protein. Diabetic patients with dysregulated insulin signalling are at increased risk of developing AD. Further, several animal models of diabetes show increased Aβ expression and hyperphosphorylated tau. As we have shown recently, the anti-diabetic drug metformin is capable of dephosphorylating tau at AD-relevant phospho-sites. Here, we investigated the effect of metformin on the main amyloidogenic enzyme BACE1 and, thus, on the production of Aβ peptides, the second pathological hallmark of AD. We find similar results in cultures of primary neurons, a human cell line model of AD and in vivo in mice. We show that treatment with metformin decreases BACE1 protein expression by interfering with an mRNA-protein complex that contains the ubiquitin ligase MID1, thereby reducing BACE1 activity. Together with our previous findings these results indicate that metformin may target both pathological hallmarks of AD and may be of therapeutic value for treating and/or preventing AD.     

Experimental Diabetes Mellitus Exacerbates Tau Pathology in a Transgenic Mouse Model of Alzheimer's Disease

Diabetes mellitus (DM) is characterized by hyperglycemia caused by a lack of insulin, insulin resistance, or both. There is increasing evidence that insulin also plays a role in Alzheimer''s disease (AD) as it is involved in the metabolism of β-amyloid (Aβ) and tau, two proteins that form Aβ plaques and neurofibrillary tangles (NFTs), respectively, the hallmark lesions in AD. Here, we examined the effects of experimental DM on a pre-existing tau pathology in the pR5 transgenic mouse strain that is characterized by NFTs. pR5 mice express P301L mutant human tau that is associated with dementia. Experimental DM was induced by administration of streptozotocin (STZ), which causes insulin deficiency. We determined phosphorylation of tau, using immunohistochemistry and Western blotting. Solubility of tau was determined upon extraction with sarkosyl and formic acid, and Gallyas silver staining was employed to reveal NFTs. Insulin depletion by STZ administration in six months-old non-transgenic mice causes increased tau phosphorylation, without its deposition or NFT formation. In contrast, in pR5 mice this results in massive deposition of hyperphosphorylated, insoluble tau. Furthermore, they develop a pronounced tau-histopathology, including NFTs at this early age, while the pathology in sham-treated pR5 mice is moderate. Whereas experimental DM did not result in deposition of hyperphosphorylated tau in non-transgenic mice, a predisposition to develop a tau pathology in young pR5 mice was both sufficient and necessary to exacerbate tau deposition and NFT formation. Hence, DM can accelerate onset and increase severity of disease in individuals with a predisposition to developing tau pathology.     

Humanized Tau Mice with Regionalized Amyloid Exhibit Behavioral Deficits but No Pathological Interaction

Alzheimer’s disease (AD) researchers have struggled for decades to draw a causal link between extracellular Aβ aggregation and intraneuronal accumulation of microtubule-associated protein tau. The amyloid cascade hypothesis posits that Aβ deposition promotes tau hyperphosphorylation, tangle formation, cell loss, vascular damage, and dementia. While the genetics of familial AD and the pathological staging of sporadic disease support this sequence of events, attempts to examine the molecular mechanism in transgenic animal models have largely relied on models of other inherited tauopathies as the basis for testing the interaction with Aβ. In an effort to more accurately model the relationship between Aβ and wild-type tau in AD, we intercrossed mice that overproduce human Aβ with a tau substitution model in which all 6 isoforms of the human protein are expressed in animals lacking murine tau. We selected an amyloid model in which pathology was biased towards the entorhinal region so that we could further examine whether the anticipated changes in tau phosphorylation occurred at the site of Aβ deposition or in synaptically connected regions. We found that Aβ and tau had independent effects on locomotion, learning, and memory, but found no behavioral evidence for an interaction between the two transgenes. Moreover, we saw no indication of amyloid-induced changes in the phosphorylation or aggregation of human tau either within the entorhinal area or elsewhere. These findings suggest that robust amyloid pathology within the medial temporal lobe has little effect on the metabolism of wild type human tau in this model.     

Synapses and Alzheimer’s Disease

Alzheimer’s disease (AD) is a major cause of dementia in the elderly. Pathologically, AD is characterized by the accumulation of insoluble aggregates of Aβ-peptides that are proteolytic cleavage products of the amyloid-β precursor protein (“plaques”) and by insoluble filaments composed of hyperphosphorylated tau protein (“tangles”). Familial forms of AD often display increased production of Aβ peptides and/or altered activity of presenilins, the catalytic subunits of γ-secretase that produce Aβ peptides. Although the pathogenesis of AD remains unclear, recent studies have highlighted two major themes that are likely important. First, oligomeric Aβ species have strong detrimental effects on synapse function and structure, particularly on the postsynaptic side. Second, decreased presenilin function impairs synaptic transmission and promotes neurodegeneration. The mechanisms underlying these processes are beginning to be elucidated, and, although their relevance to AD remains debated, understanding these processes will likely allow new therapeutic avenues to AD.Alzheimer’s disease (AD) is a common neurodegenerative disease of the elderly, first described by the physician-pathologist Alois Alzheimer in 1907 (Maurer and Maurer 2003). Clinically, AD is characterized by progressive impairment of memory (particularly short-term memory in early stages) and other cognitive disabilities, personality changes, and ultimately, complete dependence on others. The most prevalent cause of dementia worldwide, AD afflicts >5 million people in the United States and >25 million globally (Alzheimer’s Association, http://www.alz.org). Age is the most important risk factor, with the prevalence of AD rising exponentially after 65 (Blennow et al. 2006). However, many cases of so-called AD above 80 yr of age may result from a combination of pathological dementia processes (Fotuhi et al. 2009). The apolipoprotein E (ApoE) gene is the most important genetic susceptibility factor for AD, with the relatively common ApoE4 allele (prevalence ∼16%) increasing the risk for AD threefold to fourfold in heterozygous dose (Kim et al. 2009).The histopathological hallmarks of AD are amyloid plaques (extracellular deposits consisting largely of aggregated amyloid beta [Aβ] peptide that are typically surrounded by neurons with dystrophic neurites) and neurofibrillary tangles (NFTs, intracellular filamentous aggregates of hyperphosphorylated tau, a microtubule-binding protein) (Blennow et al. 2006). The development of amyloid plaques typically precedes clinically significant symptoms by at least 10–15 yr. Amyloid plaques are found in a minority of nondemented elderly patients, who may represent a “presymptomatic” AD population. As AD progresses, cognitive function worsens, synapse loss and neuronal cell death become prominent, and there is substantial reduction in brain volume, especially in the entorhinal cortex and hippocampus. The best correlation between dementia and histopathological changes is observed with neurofibrillary tangles, whereas the relationship between the density of amyloid plaques and loss of cognition is weaker (Braak and Braak 1990; Nagy et al. 1995). In addition to amyloid plaques and neurofibrillary tangles, many AD cases exhibit widespread Lewy body pathology. (Lewy bodies are intracellular inclusion bodies that contain aggregates of α-synuclein and other proteins.) Particularly in very old patients, considerable overlap between AD, frontotemporal dementia, Lewy body dementia, and vascular disease is observed, and pure AD may be rare (Fotuhi et al. 2009).     

The chaperone domain BRICHOS prevents CNS toxicity of amyloid-β peptide in Drosophila melanogaster

Aggregation of the amyloid-β peptide (Aβ) into toxic oligomers and amyloid fibrils is linked to the development of Alzheimer’s disease (AD). Mutations of the BRICHOS chaperone domain are associated with amyloid disease and recent in vitro data show that BRICHOS efficiently delays Aβ42 oligomerization and fibril formation. We have generated transgenic Drosophila melanogaster flies that express the Aβ42 peptide and the BRICHOS domain in the central nervous system (CNS). Co-expression of Aβ42 and BRICHOS resulted in delayed Aβ42 aggregation and dramatic improvements of both lifespan and locomotor function compared with flies expressing Aβ42 alone. Moreover, BRICHOS increased the ratio of soluble:insoluble Aβ42 and bound to deposits of Aβ42 in the fly brain. Our results show that the BRICHOS domain efficiently reduces the neurotoxic effects of Aβ42, although significant Aβ42 aggregation is taking place. We propose that BRICHOS-based approaches should be explored with an aim towards the future prevention and treatment of AD.KEY WORDS: Amyloid, Alzheimer’s disease, Protein misfolding, Chaperone     

Frontiers of Model Animals for Neuroscience:Two Prosperous Aging Model Animals forPromoting Neuroscience Research

A model animal showing spontaneous onset is a useful tool for investigating the mechanism of disease. Here, I would like to introduce two aging model animals expected to be useful for neuroscience research: the senescence-accelerated mouse (SAM) and the klotho mouse. The SAM was developed as a mouse showing a senescence-related phenotype such as a short lifespan or rapid advancement of senescence. In particular, SAMP8 and SAMP10 show age-related impairment of learning and memory. SAMP8 has spontaneous spongy degeneration in the brain stem and spinal cord with aging, and immunohistochemical studies reveal excess protein expression of amyloid precursor protein and amyloid β in the brain, indicating that SAMP8 is a model for Alzheimer’s disease. SAMP10 also shows age-related impairment of learning and memory, but it does not seem to correspond to Alzheimer’s disease because senile plaques primarily composed of amyloid β or neurofibrillary tangles primarily composed of phosphorylated tau were not observed. However, severe atrophy in the frontal cortex, entorhinal cortex, amygdala, and nucleus accumbens can be seen in this strain in an age-dependent manner, indicating that SAMP10 is a model for normal aging. The klotho mouse shows a phenotype, regulated by only one gene named α-klotho, similar to human progeria. The α-klotho gene is mainly expressed in the kidney and brain, and oxidative stress is involved in the deterioration of cognitive function of the klotho mouse. These animal models are potentially useful for neuroscience research now and in the near future.     

Characterization of a Novel Mouse Model of Alzheimer’s Disease—Amyloid Pathology and Unique β-Amyloid Oligomer Profile

Amyloid plaques composed of β-amyloid (Aβ) protein are a pathological hallmark of Alzheimer’s disease. We here report the generation and characterization of a novel transgenic mouse model of Aβ toxicity. The rTg9191 mice harbor a transgene encoding the 695 amino-acid isoform of human amyloid precursor protein (APP) with the Swedish and London mutations (APP_NLI) linked to familial Alzheimer’s disease, under the control of a tetracycline-response element, as well as a transgene encoding the tetracycline transactivator, under the control of the promoter for calcium-calmodulin kinase IIα. In these mice, APP_NLI is expressed at a level four-fold that of endogenous mouse APP and its expression is restricted to forebrain regions. Transgene expression was suppressed by 87% after two months of doxycycline administration. Histologically, we showed that (1) Aβ plaques emerged in cerebral cortex and hippocampus as early as 8 and 10.5-12.5 months of age, respectively; (2) plaque deposition progressed in an age-dependent manner, occupying up to 19% of cortex at ~25 months of age; and (3) neuropathology—such as abnormal neuronal architecture, tau hyperphosphorylation and misfolding, and neuroinflammation—was observed in the vicinity of neuritic plaques. Biochemically, we determined total Aβ production at varied ages of mice, and we showed that mice produced primarily fibrillar Aβ assemblies recognized by conformation-selective OC antibodies, but few non-fibrillar oligomers (e.g., Aβ*56) detectable by A11 antibodies. Finally, we showed that expression of the tetracycline transactivator resulted in reduced brain weight and smaller dentate-gyrus size. Collectively, these data indicate that rTg9191 mice may serve as a model for studying the neurological effects of the fibrillar Aβ assemblies in situ.     

Bapineuzumab Alters Aβ Composition: Implications for the Amyloid Cascade Hypothesis and Anti-Amyloid Immunotherapy

The characteristic neuropathological changes associated with Alzheimer’s disease (AD) and other lines of evidence support the amyloid cascade hypothesis. Viewing amyloid deposits as the prime instigator of dementia has now led to clinical trials of multiple strategies to remove or prevent their formation. We performed neuropathological and biochemical assessments of 3 subjects treated with bapineuzumab infusions. Histological analyses were conducted to quantify amyloid plaque densities, Braak stages and the extent of cerebral amyloid angiopathy (CAA). Amyloid-β (Aβ) species in frontal and temporal lobe samples were quantified by ELISA. Western blots of amyloid-β precursor protein (AβPP) and its C-terminal (CT) fragments as well as tau species were performed. Bapineuzumab-treated (Bapi-AD) subjects were compared to non-immunized age-matched subjects with AD (NI-AD) and non-demented control (NDC) cases. Our study revealed that Bapi-AD subjects exhibited overall amyloid plaque densities similar to those of NI-AD cases. In addition, CAA was moderate to severe in NI-AD and Bapi-AD patients. Although histologically-demonstrable leptomeningeal, cerebrovascular and neuroparenchymal-amyloid densities all appeared unaffected by treatment, Aβ peptide profiles were significantly altered in Bapi-AD subjects. There was a trend for reduction in total Aβ₄₂ levels as well as an increase in Aβ₄₀ which led to a corresponding significant decrease in Aβ₄₂:Aβ₄₀ ratio in comparison to NI-AD subjects. There were no differences in the levels of AβPP, CT99 and CT83 or tau species between Bapi-AD and NI-AD subjects. The remarkable alteration in Aβ profiles reveals a dynamic amyloid production in which removal and depositional processes were apparently perturbed by bapineuzumab therapy. Despite the alteration in biochemical composition, all 3 immunized subjects exhibited continued cognitive decline.     

Early-onset Formation of Parenchymal Plaque Amyloid Abrogates Cerebral Microvascular Amyloid Accumulation in Transgenic Mice

The fibrillar assembly and deposition of amyloid β (Aβ) protein, a key pathology of Alzheimer disease, can occur in the form of parenchymal amyloid plaques and cerebral amyloid angiopathy (CAA). Familial forms of CAA exist in the absence of appreciable parenchymal amyloid pathology. The molecular interplay between parenchymal amyloid plaques and CAA is unclear. Here we investigated how early-onset parenchymal amyloid plaques impact the development of microvascular amyloid in transgenic mice. Tg-5xFAD mice, which produce non-mutated human Aβ and develop early-onset parenchymal amyloid plaques, were bred to Tg-SwDI mice, which produce familial CAA mutant human Aβ and develop cerebral microvascular amyloid. The bigenic mice presented with an elevated accumulation of Aβ and fibrillar amyloid in the brain compared with either single transgenic line. Tg-SwDI/Tg-5xFAD mice were devoid of microvascular amyloid, the prominent pathology of Tg-SwDI mice, but exhibited larger parenchymal amyloid plaques compared with Tg-5xFAD mice. The larger parenchymal amyloid deposits were associated with a higher loss of cortical neurons and elevated activated microglia in the bigenic Tg-SwDI/Tg-5xFAD mice. The periphery of parenchymal amyloid plaques was largely composed of CAA mutant Aβ. Non-mutated Aβ fibril seeds promoted CAA mutant Aβ fibril formation in vitro. Further, intrahippocampal administration of biotin-labeled CAA mutant Aβ peptide accumulated on and adjacent to pre-existing parenchymal amyloid plaques in Tg-5xFAD mice. These findings indicate that early-onset parenchymal amyloid plaques can serve as a scaffold to capture CAA mutant Aβ peptides and prevent their accumulation in cerebral microvessels.     

Beneficial Effect of Antibodies against β- Secretase Cleavage Site of App on Alzheimer’s-Like Pathology in Triple-Transgenic Mice

The toxicity of amyloid β and tau, the two hallmark proteins in Alzheimer’s disease (AD), has been extensively studied individually. Recently new data suggest their possible interactions and synergistic effects in the disease. In this study, we investigate the ability of antibodies against the β secretase cleavage site on APP, named BBS1, to affect tau pathology, besides their well established effect on intracellular Aβ and amyloid load. For this purpose we treated the triple transgenic mice model of AD (3x Tg-AD) with mAb BBS1 intracerebroventricularly, using mini osmotic pumps for one month. The experimental data demonstrated reduction in total and phosphorylated tau levels, explained by significant reduction in GSK3β which phosphorylates tau on sites recognized by antibodies against PHF1 and AT-8. The treatment increased the cognitive capabilities and reduced the brain inflammation levels which accompany AD pathology. The data showing that tau pathology was significantly reduced by BBS1 antibodies suggest a close interaction between tau and Aβ in the development of AD, and may serve as an efficient novel immunotherapy against both hallmarks of this disease.     

Dipeptidyl peptidase 4 contributes to Alzheimer’s disease–like defects in a mouse model and is increased in sporadic Alzheimer’s disease brains

The amyloid cascade hypothesis, which proposes a prominent role for full-length amyloid β peptides in Alzheimer’s disease, is currently being questioned. In addition to full-length amyloid β peptide, several N-terminally truncated fragments of amyloid β peptide could well contribute to Alzheimer’s disease setting and/or progression. Among them, pyroGlu3–amyloid β peptide appears to be one of the main components of early anatomical lesions in Alzheimer’s disease–affected brains. Little is known about the proteolytic activities that could account for the N-terminal truncations of full-length amyloid β, but they appear as the rate-limiting enzymes yielding the Glu3–amyloid β peptide sequence that undergoes subsequent cyclization by glutaminyl cyclase, thereby yielding pyroGlu3–amyloid β. Here, we investigated the contribution of dipeptidyl peptidase 4 in Glu3–amyloid β peptide formation and the functional influence of its genetic depletion or pharmacological blockade on spine maturation as well as on pyroGlu3–amyloid β peptide and amyloid β 42–positive plaques and amyloid β 42 load in the triple transgenic Alzheimer’s disease mouse model. Furthermore, we examined whether reduction of dipeptidyl peptidase 4 could rescue learning and memory deficits displayed by these mice. Our data establish that dipeptidyl peptidase 4 reduction alleviates anatomical, biochemical, and behavioral Alzheimer’s disease–related defects. Furthermore, we demonstrate that dipeptidyl peptidase 4 activity is increased early in sporadic Alzheimer’s disease brains. Thus, our data demonstrate that dipeptidyl peptidase 4 participates in pyroGlu3–amyloid β peptide formation and that targeting this peptidase could be considered as an alternative strategy to interfere with Alzheimer’s disease progression.     

Focus: The Aging Brain: Amyloid-beta Alzheimer targets — protein processing,lipid rafts,and amyloid-beta pores

Amyloid beta (Aβ), the hallmark of Alzheimer’s Disease (AD), now appears to be deleterious in its low number aggregate form as opposed to the macroscopic Aβ fibers historically seen postmortem. While Alzheimer targets, such as the tau protein, amyloid precursor protein (APP) processing, and immune system activation continue to be investigated, the recent discovery that amyloid beta aggregates at lipid rafts and likely forms neurotoxic pores has led to a new paradigm regarding why past therapeutics may have failed and how to design the next round of compounds for clinical trials. An atomic resolution understanding of Aβ aggregates, which appear to exist in multiple conformations, is most desirable for future therapeutic development. The investigative difficulties, structures of these small Aβ aggregates, and current therapeutics are summarized in this review.     

Drosophila Eye Model to Study Neuroprotective Role of CREB Binding Protein (CBP) in Alzheimer’s Disease

Background

The progressive neurodegenerative disorder Alzheimer’s disease (AD) manifests as loss of cognitive functions, and finally leads to death of the affected individual. AD may result from accumulation of amyloid plaques. These amyloid plaques comprising of amyloid-beta 42 (Aβ42) polypeptides results from the improper cleavage of amyloid precursor protein (APP) in the brain. The Aβ42 plaques have been shown to disrupt the normal cellular processes and thereby trigger abnormal signaling which results in the death of neurons. However, the molecular-genetic mechanism(s) responsible for Aβ42 mediated neurodegeneration is yet to be fully understood.

Methodology/Principal Findings

We have utilized Gal4/UAS system to develop a transgenic fruit fly model for Aβ42 mediated neurodegeneration. Targeted misexpression of human Aβ42 in the differentiating photoreceptor neurons of the developing eye of transgenic fly triggers neurodegeneration. This progressive neurodegenerative phenotype resembles Alzheimer’s like neuropathology. We identified a histone acetylase, CREB Binding Protein (CBP), as a genetic modifier of Aβ42 mediated neurodegeneration. Targeted misexpression of CBP along with Aβ42 in the differentiating retina can significantly rescue neurodegeneration. We found that gain-of-function of CBP rescues Aβ42 mediated neurodegeneration by blocking cell death. Misexpression of Aβ42 affects the targeting of axons from retina to the brain but misexpression of full length CBP along with Aβ42 can restore this defect. The CBP protein has multiple domains and is known to interact with many different proteins. Our structure function analysis using truncated constructs lacking one or more domains of CBP protein, in transgenic flies revealed that Bromo, HAT and polyglutamine (BHQ) domains together are required for the neuroprotective function of CBP. This BHQ domain of CBP has not been attributed to promote survival in any other neurodegenerative disorders.

Conclusions/Significance

We have identified CBP as a genetic modifier of Aβ42 mediated neurodegeneration. Furthermore, we have identified BHQ domain of CBP is responsible for its neuroprotective function. These studies may have significant bearing on our understanding of genetic basis of AD.     

Phloroglucinol Attenuates the Cognitive Deficits of the 5XFAD Mouse Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common form of dementia among the elderly. Neuritic plaques whose primary component is amyloid beta peptide (Aβ) and neurofibrillary tangles which are composed of hyperphosphorylated tau, are known to be the neuropathological hallmarks of AD. In addition, impaired synaptic plasticity in neuronal networks is thought to be important mechanism underlying for the cognitive deficits observed in AD. Although various causative factors, including excitotoxicity, mitochondrial dysregulation and oxidative damage caused by Aβ, are involved in early onset of AD, fundamental therapeutics that can modify the progression of this disease are not currently available. In the present study, we investigated whether phloroglucinol (1, 3, 5—trihydroxybenzene), a component of phlorotannins, which are plentiful in Ecklonia cava, a marine brown alga species, displays therapeutic activities in AD. We found that phloroglucinol attenuates the increase in reactive oxygen species (ROS) accumulation induced by oligomeric Aβ_1–42 (Aβ_1–42) treatment in HT-22, hippocampal cell line. In addition, phloroglucinol was shown to ameliorate the reduction in dendritic spine density induced by Aβ_1–42 treatment in rat primary hippocampal neuron cultures_. We also found that the administration of phloroglucinol to the hippocampal region attenuated the impairments in cognitive dysfunction observed in 22-week-old 5XFAD (Tg6799) mice, which are used as an AD animal model. These results indicate that phloroglucinol displays therapeutic potential for AD by reducing the cellular ROS levels.     

Microglial PD‐1 stimulation by astrocytic PD‐L1 suppresses neuroinflammation and Alzheimer’s disease pathology

Chronic neuroinflammation is a pathogenic component of Alzheimer’s disease (AD) that may limit the ability of the brain to clear amyloid deposits and cellular debris. Tight control of the immune system is therefore key to sustain the ability of the brain to repair itself during homeostasis and disease. The immune‐cell checkpoint receptor/ligand pair PD‐1/PD‐L1, known for their inhibitory immune function, is expressed also in the brain. Here, we report upregulated expression of PD‐L1 and PD‐1 in astrocytes and microglia, respectively, surrounding amyloid plaques in AD patients and in the APP/PS1 AD mouse model. We observed juxtamembrane shedding of PD‐L1 from astrocytes, which may mediate ectodomain signaling to PD‐1‐expressing microglia. Deletion of microglial PD‐1 evoked an inflammatory response and compromised amyloid‐β peptide (Aβ) uptake. APP/PS1 mice deficient for PD‐1 exhibited increased deposition of Aβ, reduced microglial Aβ uptake, and decreased expression of the Aβ receptor CD36 on microglia. Therefore, ineffective immune regulation by the PD‐1/PD‐L1 axis contributes to Aβ plaque deposition during chronic neuroinflammation in AD.     

FLZ Alleviates the Memory Deficits in Transgenic Mouse Model of Alzheimer’s Disease via Decreasing Beta-Amyloid Production and Tau Hyperphosphorylation

Alzheimer’s disease (AD) is the most common cause of dementia worldwide and mainly characterized by the aggregated β-amyloid (Aβ) and hyperphosphorylated tau. FLZ is a novel synthetic derivative of natural squamosamide and has been proved to improve memory deficits in dementia animal models. In this study, we aimed to investigate the mechanisms of FLZ’s neuroprotective effect in APP/PS1 double transgenic mice and SH-SY5Y (APPwt/swe) cells. The results showed that treatment with FLZ significantly improved the memory deficits of APP/PS1 transgenic mice and decreased apoptosis of SH-SY5Y (APPwt/swe) cells. FLZ markedly attenuated Aβ accumulation and tau phosphorylation both in vivo and in vitro. Mechanistic study showed that FLZ interfered APP processing, i.e., FLZ decreased β-amyloid precursor protein (APP) phosphorylation, APP-carboxy-terminal fragment (APP-CTF) production and β-amyloid precursor protein cleaving enzyme 1 (BACE1) expression. These results indicated that FLZ reduced Aβ production through inhibiting amyloidogenic pathway. The mechanistic study about FLZ’s inhibitory effect on tau phosphorylation revealed t the involvement of Akt/glycogen synthase kinase 3β (GSK3β) pathway. FLZ treatment increased Akt activity and inhibited GSK3β activity both in vivo and in vitro. The inhibitory effect of FLZ on GSK3β activity and tau phosphorylation was suppressed by inhibiting Akt activity, indicating that Akt/GSK3β pathway might be the possible mechanism involved in the inhibitory effect of FLZ on tau hyperphosphorylation. These results suggested FLZ might be a potential anti-AD drug as it not only reduced Aβ production via inhibition amyloidogenic APP processing pathway, but also attenuated tau hyperphosphoylation mediated by Akt/GSK3β.     

Advances on the Understanding of the Origins of Synaptic Pathology in AD

Although Alzheimer’s disease (AD) was first discovered a century ago, we are still facing a lack of definitive diagnosis during the patient’s lifetime and are unable to prescribe a curative treatment. However, the past 10 years have seen a “revamping” of the main hypothesis about AD pathogenesis and the hope to foresee possible treatment. AD is no longer considered an irreversible disease. A major refinement of the classic β-amyloid cascade describing amyloid fibrils as neurotoxins has been made to integrate the key scientific evidences demonstrating that the first pathological event occurring in AD early stages affects synaptic function and maintenance. A concept fully compatible with synapse loss being the best pathological correlate of AD rather than other described neuropathological hallmarks (amyloid plaques, neurofibrillary tangles or neuronal death). The notion that synaptic alterations might be reverted, thus offering a potential curability, was confirmed by immunotherapy experiments targeting β-amyloid protein in transgenic AD mice in which cognitive functions were improved despite no reduction in the amyloid plaques burden. The updated amyloid cascade now integrates the synapse failure triggered by soluble Aβ-oligomers. Still no consensus has been reached on the most toxic Aβ conformations, neither on their site of production nor on their extra- versus intra-cellular actions. Evidence shows that soluble Aβ oligomers or ADDLs bind selectively to neurons at their synaptic loci, and trigger major changes in synapse composition and morphology, which ultimately leads to dendritic spine loss. However, the exact mechanism is not yet fully understood but is suspected to involve some membrane receptor(s).