The collapse of neural networks important for memory and cognition, including death of neurons and degeneration of synapses, causes the debilitating dementia associated with Alzheimer’s disease (AD). ...We suggest that synaptic changes are central to the disease process. Amyloid beta and tau form fibrillar lesions that are the classical hallmarks of AD. Recent data indicate that both molecules may have normal roles at the synapse, and that the accumulation of soluble toxic forms of the proteins at the synapse may be on the critical path to neurodegeneration. Further, the march of neurofibrillary tangles through brain circuits appears to take advantage of recently described mechanisms of transsynaptic spread of pathological forms of tau. These two key phenomena, synapse loss and the spread of pathology through the brain via synapses, make it critical to understand the physiological and pathological roles of amyloid beta and tau at the synapse.
Synapses, the connections between neurons, are key players in causing dementia in Alzheimer’s disease. In this issue, Spires-Jones and Hyman review research progress showing that pathological proteins in Alzheimer’s spread through the brain via synaptic circuits and cause synapse dysfunction and loss.
It is estimated that 40% of dementia cases could be prevented by modification of lifestyle factors that associate with disease risk. One of these potentially modifiable lifestyle factors is social ...isolation. In this review, we discuss what is known about associations between social isolation and Alzheimer's disease, the most common cause of dementia. This is particularly relevant in the time of the COVID‐19 pandemic when social isolation has been enforced with potential emerging negative impacts on cognition. While there are neurobiological mechanisms emerging that may account for the observed epidemiological associations between social isolation and Alzheimer's disease, more fundamental research is needed to fully understand the brain changes induced by isolation that may make people vulnerable to disease.
The authors review the potential bidirectional association between social isolation and dementia and explore potential neurobiological mechanisms that may mediate this association.
Neurofibrillary tangles advance from layer II of the entorhinal cortex (EC-II) toward limbic and association cortices as Alzheimer's disease evolves. However, the mechanism involved in this ...hierarchical pattern of disease progression is unknown. We describe a transgenic mouse model in which overexpression of human tau P301L is restricted to EC-II. Tau pathology progresses from EC transgene-expressing neurons to neurons without detectable transgene expression, first to EC neighboring cells, followed by propagation to neurons downstream in the synaptic circuit such as the dentate gyrus, CA fields of the hippocampus, and cingulate cortex. Human tau protein spreads to these regions and coaggregates with endogenous mouse tau. With age, synaptic degeneration occurs in the entorhinal target zone and EC neurons are lost. These data suggest that a sequence of progressive misfolding of tau proteins, circuit-based transfer to new cell populations, and deafferentation induced degeneration are part of a process of tau-induced neurodegeneration.
► Tau pathology propagates to surrounding mRNA-negative cells (neurons and astrocytes) ► Human tau protein spreads misfolding to downstream synaptically connected areas ► Human tau seeds misfolding of mouse tau ► mRNA-negative DG neurons developed tangles
Alzheimer's tangles occur in anatomically connected regions. de Calignon et al. expressed tauP301L exclusively in mouse entorhinal cortex and found that with age, tangles occur both locally and in entorhinal projection targets, suggesting that tau may propagate across synapses.
Pathological tau leads to dementia and neurodegeneration in tauopathies, including Alzheimer’s disease. It has been shown to disrupt cellular and synaptic functions, yet its effects on the function ...of the intact neocortical network remain unknown. Using in vivo intracellular and extracellular recordings, we measured ongoing activity of neocortical pyramidal cells during various arousal states in the rTg4510 mouse model of tauopathy, prior to significant cell death, when only a fraction of the neurons show pathological tau. In transgenic mice, membrane potential oscillations are slower during slow-wave sleep and under anesthesia. Intracellular recordings revealed that these changes are due to longer Down states and state transitions of membrane potentials. Firing rates of transgenic neurons are reduced, and firing patterns within Up states are altered, with longer latencies and inter-spike intervals. By changing the activity patterns of a subpopulation of affected neurons, pathological tau reduces the activity of the neocortical network.
•Pathological tau disrupts the activity of single cells and neocortical networks•Pathological tau alters neocortical neuronal oscillatory patterns•Pathological tau affects firing patterns of neocortical pyramidal cells
Menkes-Caspi et al. show that the activity of cortical neurons is reduced in tau-transgenic mice, including in neurons without detectable pathological tau. The pathological effects on a group of neurons are amplified and propagated through the entire cortical network.
Neurodegenerative diseases such as Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTD), Lewy body disease (LBD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) have ...in common that protein aggregates represent pathological hallmark lesions. Amyloid β-protein, τ-protein, α-synuclein, and TDP-43 are the most frequently aggregated proteins in these disorders. Although they are assumed to form disease-characteristic aggregates, such as amyloid plaques and neurofibrillary tangles in AD or Lewy bodies in LBD/PD, they are not restricted to these clinical presentations. They also occur in non-diseased individuals and can co-exist in the same brain without or with a clinical picture of a distinct dementing or movement disorder. In this review, we discuss the co-existence of these pathologies and potential additive effects in the human brain as well as related functional findings on cross-seeding and molecular interactions between these aggregates/proteins. We conclude that there is evidence for interactions at the molecular level as well as for additive effects on brain damage by multiple pathologies occurring in different functionally important neurons. Based upon this information, we hypothesize a cascade of events that may explain general mechanisms in the development of neurodegenerative disorders: (1) distinct lesions are a prerequisite for the development of a distinct disease (e.g., primary age-related tauopathy for AD), (2) disease-specific pathogenic events further trigger the development of a specific disease (e.g., Aβ aggregation in AD that exaggerate further Aβ and AD-related τ pathology), (3) the symptomatic disease manifests, and (4) neurodegenerative co-pathologies may be either purely coincidental or (more likely) have influence on the disease development and/or its clinical presentation.
The symptoms of Alzheimer disease reflect a loss of neural circuit integrity in the brain, but neurons do not work in isolation. Emerging evidence suggests that the intricate balance of interactions ...between neurons, astrocytes, microglia and vascular cells required for healthy brain function becomes perturbed during the disease, with early changes likely protecting neural circuits from damage, followed later by harmful effects when the balance cannot be restored. Moving beyond a neuronal focus to understand the complex cellular interactions in Alzheimer disease and how these change throughout the course of the disease may provide important insight into developing effective therapeutics.
Background and purpose
Synapse degeneration in Alzheimer's disease (AD) correlates strongly with cognitive decline. There is well‐established excitatory synapse loss in AD with known contributions of ...pathological amyloid beta (Aβ) to excitatory synapse dysfunction and loss. Despite clear changes in circuit excitability in AD and model systems, relatively little is known about pathology in inhibitory synapses.
Methods
Here human postmortem brain samples (n = 5 control, 10 AD cases) from temporal and occipital cortices were examined to investigate whether inhibitory synapses and neurons are lost in AD and whether Aβ may contribute to inhibitory synapse degeneration. Inhibitory neurons were counted in all six cortical layers using stereology software, and array tomography was used to examine synapse density and the accumulation of Aβ in synaptic terminals.
Results
Differing inhibitory neuron densities were observed in the different cortical layers. The highest inhibitory neuron density was observed in layer 4 in both brain regions and the visual cortex had a higher inhibitory neuron density than the temporal cortex. There was significantly lower inhibitory neuron density in AD than in control cases in all six cortical layers. High‐resolution array tomography imaging revealed plaque‐associated loss of inhibitory synapses and accumulation of Aβ in a small subset of inhibitory presynaptic terminals with the most accumulation near amyloid plaques.
Conclusions
Inhibitory neuron and synapse loss in AD may contribute to disrupted excitatory/inhibitory balance and cognitive decline. Future work is warranted to determine whether targeting inhibitory synapse loss could be a useful therapeutic strategy.
Kurucu et al. used high‐resolution array tomography imaging to observe inhibitory synapse loss in the temporal cortex of Alzheimer's disease brains. This three‐dimensional reconstruction shows inhibitory synapse loss around amyloid plaques. Presynaptic terminals are labelled with synaptophysin (green), glutamic acid decarboxylase 65/67 labels inhibitory neuron processes (red—inhibitory synapses are both red and green), amyloid beta shows plaques and synaptic accumulation of oligomers (grey) and 4',6‐diamino‐2‐phenylindole (DAPI) labels nuclei (blue).
Tau and amyloid beta (Aβ) are the prime suspects for driving pathology in Alzheimer’s disease (AD) and, as such, have become the focus of therapeutic development. Recent research, however, shows that ...these proteins have been highly conserved throughout evolution and may have crucial, physiological roles. Such functions may be lost during AD progression or be unintentionally disrupted by tau- or Aβ-targeting therapies. Tau has been revealed to be more than a simple stabiliser of microtubules, reported to play a role in a range of biological processes including myelination, glucose metabolism, axonal transport, microtubule dynamics, iron homeostasis, neurogenesis, motor function, learning and memory, neuronal excitability, and DNA protection. Aβ is similarly multifunctional, and is proposed to regulate learning and memory, angiogenesis, neurogenesis, repair leaks in the blood–brain barrier, promote recovery from injury, and act as an antimicrobial peptide and tumour suppressor. This review will discuss potential physiological roles of tau and Aβ, highlighting how changes to these functions may contribute to pathology, as well as the implications for therapeutic development. We propose that a balanced consideration of both the physiological and pathological roles of tau and Aβ will be essential for the design of safe and effective therapeutics.
Neurodegenerative tauopathies are marked by their common pathologic feature of aggregates formed of hyperphosphorylated tau protein, which are associated with synapse and neuronal loss. Changes in ...tau conformation result in both loss of normal function and gain of fibrillogenicity that leads to aggregation. Here, we discuss the pathophysiology of tau and emerging evidence of how changes in this protein might ultimately lead to neuronal death. In particular, based on recent evidence, we propose that a non-apoptotic caspase-associated form of death is occurring in tauopathy.
Alzheimer's disease: synapses gone cold Koffie, Robert M; Hyman, Bradley T; Spires-Jones, Tara L
Molecular neurodegeneration,
08/2011, Volume:
6, Issue:
1
Journal Article
Peer reviewed
Open access
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by insidious cognitive decline and memory dysfunction. Synapse loss is the best pathological correlate of cognitive ...decline in AD and mounting evidence suggests that AD is primarily a disease of synaptic dysfunction. Soluble oligomeric forms of amyloid beta (Aβ), the peptide that aggregates to form senile plaques in the brain of AD patients, have been shown to be toxic to neuronal synapses both in vitro and in vivo. Aβ oligomers inhibit long-term potentiation (LTP) and facilitate long-term depression (LTD), electrophysiological correlates of memory formation. Furthermore, oligomeric Aβ has also been shown to induce synapse loss and cognitive impairment in animals. The molecular underpinnings of these observations are now being elucidated, and may provide clear therapeutic targets for effectively treating the disease. Here, we review recent findings concerning AD pathogenesis with a particular focus on how Aβ impacts synapses.
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