Janet E. Carter

Intracerebral Transplantation of Bone Marrow‐Derived Mesenchymal Stem Cells Reduces Amyloid‐Beta Deposition and Rescues Memory Deficits in Alzheimer's Disease Mice by Modulation of Immune Responses

Alzheimers disease (AD) is characterized by the deposition of amyloid‐β peptide (Aβ) and the formation of neurofibrillary tangles. Transplantation of bone marrow‐derived mesenchymal stem cells (BM‐MSCs) has been suggested as a potential therapeutic approach to prevent various neurodegenerative disorders, including AD. However, the actual therapeutic impact of BM‐MSCs and their mechanism of action in AD have not yet been ascertained. The aim of this study was therefore to evaluate the therapeutic effect of BM‐MSC transplantation on the neuropathology and memory deficits in amyloid precursor protein (APP) and presenilin one (PS1) double‐transgenic mice. Here we show that intracerebral transplantation of BM‐MSCs into APP/PS1 mice significantly reduced amyloid β‐peptide (Aβ) deposition. Interestingly, these effects were associated with restoration of defective microglial function, as evidenced by increased Aβ‐degrading factors, decreased inflammatory responses, and elevation of alternatively activated microglial markers. Furthermore, APP/PS1 mice treated with BM‐MSCs had decreased tau hyperphosphorylation and improved cognitive function. In conclusion, BM‐MSCs can modulate immune/inflammatory responses in AD mice, ameliorate their pathophysiology, and improve the cognitive decline associated with Aβ deposits. These results demonstrate that BM‐MSCs are a potential new therapeutic agent for AD. STEM CELLS 2010;28:329–343

Intracerebral transplantation of mesenchymal stem cells into acid sphingomyelinase–deficient mice delays the onset of neurological abnormalities and extends their life span

Types A and B Niemann-Pick disease (NPD) are lysosomal storage disorders resulting from loss of acid sphingomyelinase (ASM) activity. We have used a knockout mouse model of NPD (ASMKO mice) to evaluate the effects of direct intracerebral transplantation of bone marrow-derived mesenchymal stem cells (MSCs) on the progression of neurological disease in this disorder. MSCs were transduced with a retroviral vector to overexpress ASM and were injected into the hippocampus and cerebellum of 3-week-old ASMKO pups. Transplanted cells migrated away from the injection sites and survived at least 6 months after transplantation. Seven of 8 treated mice, but none of the untreated controls, survived for > or = 7 months after transplant. Survival times were greater in sex-matched than in sex-mismatched transplants. Transplantation significantly delayed the Purkinje cell loss that is characteristic of NPD, although the protective effect declined with distance from the injection site. Overall ASM activity in brain homogenates was low, but surviving Purkinje cells contained the retrovirally expressed human enzyme, and transplanted animals showed a reduction in cerebral sphingomyelin. These results reveal the potential of treating neurodegenerative lysosomal storage disorders by intracerebral transplantation of bone marrow-derived MSCs.

Human umbilical cord blood-derived mesenchymal stem cells improve neuropathology and cognitive impairment in an Alzheimer's disease mouse model through modulation of neuroinflammation

Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSC) have a potential therapeutic role in the treatment of neurological disorders, but their current clinical usage and mechanism of action has yet to be ascertained in Alzheimers disease (AD). Here we report that hUCB-MSC transplantation into amyloid precursor protein (APP) and presenilin1 (PS1) double-transgenic mice significantly improved spatial learning and memory decline. Furthermore, amyloid-β peptide (Aβ) deposition, β-secretase 1 (BACE-1) levels, and tau hyperphosphorylation were dramatically reduced in hUCB-MSC transplanted APP/PS1 mice. Interestingly, these effects were associated with reversal of disease-associated microglial neuroinflammation, as evidenced by decreased microglia-induced proinflammatory cytokines, elevated alternatively activated microglia, and increased anti-inflammatory cytokines. These findings lead us to suggest that hUCB-MSC produced their sustained neuroprotective effect by inducing a feed-forward loop involving alternative activation of microglial neuroinflammation, thereby ameliorating disease pathophysiology and reversing the cognitive decline associated with Aβ deposition in AD mice.

Bone Marrow‐Derived Mesenchymal Stem Cells Promote Neuronal Networks with Functional Synaptic Transmission After Transplantation into Mice with Neurodegeneration

Recent studies have shown that bone marrow‐derived MSCs (BM‐MSCs) improve neurological deficits when transplanted into animal models of neurological disorders. However, the precise mechanism by which this occurs remains unknown. Herein we demonstrate that BM‐MSCs are able to promote neuronal networks with functional synaptic transmission after transplantation into Niemann‐Pick disease type C (NP‐C) mouse cerebellum. To address the mechanism by which this occurs, we used gene microarray, whole‐cell patch‐clamp recordings, and immunohistochemistry to evaluate expression of neurotransmitter receptors on Purkinje neurons in the NP‐C cerebellum. Gene microarray analysis revealed upregulation of genes involved in both excitatory and inhibitory neurotransmission encoding subunits of the ionotropic glutamate receptors (α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid, AMPA) GluR4 and GABAA receptor β2. We also demonstrated that BM‐MSCs, when originated by fusion‐like events with existing Purkinje neurons, develop into electrically active Purkinje neurons with functional synaptic formation. This study provides the first in vivo evidence that upregulation of neurotransmitter receptors may contribute to synapse formation via cell fusion‐like processes after BM‐MSC transplantation into mice with neurodegenerative disease.

The therapeutic potential of human umbilical cord blood-derived mesenchymal stem cells in Alzheimer's disease

The neuropathological hallmarks of Alzheimers disease (AD) include the presence of extracellular amyloid-beta peptide (Abeta) in the form of amyloid plaques in the brain parenchyma and neuronal loss. The mechanism associated with neuronal death by amyloid plaques is unclear but oxidative stress and glial activation has been implicated. Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) are being scrutinized as a potential therapeutic tool to prevent various neurodegenerative diseases including AD. However, the therapeutic impact of hUCB-MSCs in AD has not yet been reported. Here we undertook in vitro work to examine the potential impact of hUCB-MSCs treatment on neuronal loss using a paradigm of cultured hippocampal neurons treated with Abeta. We confirmed that hUCB-MSCs co-culture reduced the hippocampal apoptosis induced by Abeta treatment. Moreover, in an acute AD mouse model to directly test the efficacy of hUCB-MSCs treatment on AD-related cognitive and neuropathological outcomes, we demonstrated that markers of glial activation, oxidative stress and apoptosis levels were decreased in AD mouse brain. Interestingly, hUCB-MSCs treated AD mice demonstrated cognitive rescue with restoration of learning/memory function. These data suggest that hUCB-MSCs warrant further investigation as a potential therapeutic agent in AD.

Depression in older adults

#### Summary pointsnnDepression is a major contributor to healthcare costs and is projected to be the leading cause of disease burden in middle and higher income countries by the year 2030.w1 Depression in later life, traditionally defined as age older than 65, is associated with disability, increased mortality, and poorer outcomes from physical illness. Most clinicians will encounter older patients with depression in their day to day practice, but although treatment is as effective for older patients as for younger adults, the condition is often under-recognised and under-treated. According to WHO data, proportionately more people aged over 65 commit suicide than any other age group, and most have major depression. Older people who attempt suicide are more likely to die than younger people, while in those who survive, prognosis is worse for older adults.1nnWith a progressively ageing population worldwide, identification and treatment of depression in older adults becomes increasingly important, especially as older patients may have different presentations and needs than younger ones. We consider recent systematic reviews, meta-analyses, and randomised controlled trials to …

Acid sphingomyelinase modulates the autophagic process by controlling lysosomal biogenesis in Alzheimer’s disease

Acid sphingomyelinase activity is increased in brain and plasma of mice and patients with Alzheimer’s disease and its inhibition represents a potential new therapeutic intervention for this disease.

Differentiation of frontotemporal dementia from dementia with Lewy bodies using FP-CIT SPECT

Introduction There is increasing evidence that imaging with [123I]FP-CIT SPECT is helpful in differentiating dementia with Lewy bodies (DLB) from Alzheimers disease (AD) but it is not known how well the scan performs in differentiating DLB from frontotemporal dementia (FTD). Method We compared the striatal dopamine transporter (DAT) binding in FTD (n=12), DLB (n=10) and AD (n=9) by visually rating the caudate and putamen on [123I]FP-CIT SPECT scans. Results The majority (9/10) of DLB cases had an abnormal scan and a significant reduction of uptake of DAT binding in the putamen and the caudate. A third (4/12) of the FTD cases also had an abnormal scan and a significant reduction in uptake in the putamen and the caudate. In contrast, only one out of nine AD cases had an abnormal scan. Significant differences were found when comparisons were made between the groups for visual analysis of the entire scan (p=0.001) and the four regions of interest (p=0.001 – 0.013). In contrast to the AD group (specificity of scan 89%), the specificity of [123I]FP-CIT SPECT scans was reduced in the FTD group to 67%. Three quarters of the study population had at least one extrapyramidal motor sign (EPMS), with bradykinesia being the most common EPMS in both FTD (83%) and DLB (70%). Conclusions This study highlights to clinicians that a positive (abnormal) [123I]FP-CIT SPECT scan, even in a patient with an EPMS, does not exclude the diagnosis of FTD and emphasises the importance of a comprehensive clinical evaluation and a detailed cognitive assessment.

Cholinesterase inhibitors and memantine for symptomatic treatment of dementia

A 78 year old woman is assessed in the memory clinic. Her family feel that she has become increasingly forgetful over the past two years, misplacing objects around the house and forgetting her drugs. Her speech is repetitive, and she struggles with day to day activities such as cooking. Routine blood tests are normal, and she scores 21/30 on the mini-mental state examination (MMSE) with deficits in orientation, attention and concentration, and recall. Magnetic resonance imaging, performed to exclude other pathology, reveals global cerebral atrophy consistent with Alzheimer’s disease. In discussion with her and her family, a management plan is formulated that includes referral to the local dementia advisor and social services for day opportunities as well as prescription of a cholinesterase inhibitor.nnThe most common types of dementia are Alzheimer’s disease, vascular dementia, mixed dementia, dementia with Lewy bodies, and frontotemporal dementia. At present, four drugs are licensed in the UK for the management of Alzheimer’s disease, the cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and memantine, a partial antagonist of NMDA receptors (table 1⇓). The use of these drugs in other types of dementia has been investigated, with the most convincing evidence coming from studies of dementia with Lewy bodies and Parkinson’s disease dementia. There is currently no evidence to support the use of cholinesterase inhibitors or memantine in frontotemporal dementia or mild cognitive impairment.nnView this table:nnTable 1 nu2002Licensed indications for cholinesterase inhibitors and memantine in the UKnnnnCholinesterase inhibitors increase the availability of acetylcholine at the synaptic cleft by preventing its breakdown by the enzyme acetylcholinesterase. Galantamine also modulates nicotinic acetylcholine receptors, and rivastigmine inhibits butylcholinesterase, but the importance of these additional properties is unknown. Memantine is believed to act by reducing glutamate mediated excitotoxicity.nnIn this review we summarise the evidence and current guidance related to the use of …

Bone Marrow-Derived Mesenchymal Stem Cells Contribute to the Reduction of Amyloid-β Deposits and the Improvement of Synaptic Transmission in a Mouse Model of Pre-Dementia Alzheimer’s Disease

The remarkable potentiality of bone marrow-derived mesenchymal stem cells (BM-MSCs) after transplantation to models of neurological disease and injury has been described. We have previously published data confirming the influence of BM-MSCs on β-amyloid (Aβ) deposition in an Alzheimers disease (AD) mouse model. However, therapeutic approaches in neurological diseases such as AD, including those for BM-MSCs, are increasingly centered on the potential for prophylactic therapy in pro-dromal states where the underlying cause of the disease is apparent but functional deficits are not. In order to investigate whether BM-MSCs could have a beneficial effect in high-risk pre-dementia AD individuals, we treated young AD mice, at an age at which they display neuropathological, but not cognitive features of AD. Following a single intra-cerebral injection of BM-MSCs, interestingly, we found a significant decrease in the cerebral Aβ deposition compared with controls treated with PBS that was sustained up to 2 months post-injection. Expression of dynamin 1 and Synapsin 1, key pre-synaptic proteins associated with synaptic transmission, which are typically decreased in brains of AD patients, were considerably enhanced in the brains of AD mice treated with BM-MSCs and this response was sustained beyond 2 months. These data demonstrate that BM-MSCs produce an acute reduction in Aβ deposits and facilitate changes in key proteins required for synaptic transmission. These findings suggest that BM-MSC transplantation warrants further investigation as a potential therapy for early intervention in pro-dromal AD.