Physiological levels of Aβ may facilitate neuronal activity by presynaptic potentiation. This positive feedback loop is unlikely to escalate into aberrant network activity under normal circumstances, as increased neuronal activity would further enhance Aβ production, triggering negative postsynaptic regulation of excitatory synaptic transmission (). Dysregulation of Aβ in Alzheimer's disease could override these activity-dependent synaptic mechanisms, leading to synaptic failure and cognitive decline. Indeed, even small chronic increases in Aβ ultimately lead to synaptic depression38
. Pathologically elevated Aβ may also affect cognitive performance by inducing abnormal patterns of neuronal activity and compensatory responses at the level of neuronal circuits and networks49
. For the purposes of this discussion, we define neuronal circuits as smaller assemblies of interconnected neurons within a specific brain region and neuronal networks as larger assemblies of interconnected circuits involving different brain regions.
Our working model of Aβ-induced cognitive dysfunction proposes that high Aβ leads to aberrant excitatory network activity and compensatory inhibitory responses involving learning and memory circuits, and that both alterations contribute to cognitive decline8, 50
. Hippocampal compensatory responses may include calbindin depletion, GABAergic sprouting and ectopic expression of inhibitory neuropeptides8, 51, 52
Although the effects of Aβ on specific hippocampal glutamatergic synapses have been studied extensively, fewer investigations have focused on the effects of Aβ on neuronal circuits and more complex neuronal networks. Neuronal circuits are assembled through very large numbers of synaptic interactions between excitatory, inhibitory and neuromodulatory cells (). The overall effect of Aβ probably depends critically on the abundance of Aβ at each synapse, the intrinsic vulnerability of each synaptic type, the circuit architecture and the engagement of 'nonphysiological' targets by high levels of pathogenic Aβ assemblies. It is possible that Aβ affects excitatory and inhibitory synapses differentially, which could produce complex imbalances in circuit and network activity.
Pathologically elevated Aβ elicits abnormal patterns of neuronal activity in circuits and in wider networks in Alzheimer’s disease–related mouse models
Several recent reports in Alzheimer's disease–related mouse models suggest that pathologically elevated Aβ destabilizes neuronal activity at the circuit and network levels. We demonstrated by electroencephalogram (EEG) recording from cortical and hippocampal networks in hAPP transgenic mice that elevation of Aβ elicits epileptiform activity, including spikes and sharp waves8
(). hAPP mice also have intermittent unprovoked seizures involving diverse regions of the neocortex and hippocampus that are not accompanied by tonic or clonic motor activity. These results demonstrate that chronic exposure to pathologically elevated Aβ is sufficient to elicit epileptic activity in vivo, a conclusion that is also supported by findings obtained in other hAPP lines53, 54, 55
These aberrant patterns of neuronal activity are associated with wide fluctuations in the neuronal expression of synaptic activity–regulated gene products, such as Arc and Fos, in the dentate gyrus8
(). Consistent with these findings, in vivo calcium imaging of cortical circuits shows that hAPP and PS1 doubly transgenic (hAPP/PS1) mice have a greater proportion of hyperactive and hypoactive neurons than nontransgenic controls9
(). Notably, these Alzheimer's disease–related mouse models have reduced glutamatergic excitatory currents and synaptic loss, suggesting that high Aβ leads to aberrant patterns of neuronal activity by enhancing synchrony among the remaining glutamatergic synapses rather than by increasing excitatory synaptic activity per se.
The processes described above would be expected to diminish the amount of time neural networks spend in activity patterns that promote normal cognitive functions (). In this context, it is noteworthy that hippocampal alterations in synaptic activity-regulated proteins are tightly associated with learning and memory deficits in independent hAPP transgenic lines26, 51, 56
. Moreover, experimental manipulations that prevent seizure activity and compensatory responses in hAPP mice also prevent cognitive deficits in these models57
, suggesting that Aβ-induced aberrant network synchronization could contribute to cognitive impairments in Alzheimer's disease.
Although the incidence of seizures in individuals with late-onset Alzheimer's disease is clearly higher than that in age-matched undemented controls12, 58
, frank convulsive seizures are rare and only affect 5% to 20% of patients with Alzheimer's disease. In contrast, individuals from many pedigrees with autosomal dominant early-onset Alzheimer's disease show generalized convulsive seizures and myoclonic activity12, 59, 60, 61
. Seizures are part of the natural history of Alzheimer's disease associated with any one of over 30 different PS1 mutations59
and have been observed in 31% of FAD patients with PS2 mutations62
, 56% of patients with APP duplications61
, ~83% of pedigrees with very early-onset Alzheimer's disease (<40 years)60
, and 84% of Down syndrome patients who develop Alzheimer's disease63
. The incidence of nonconvulsive epileptiform activity in early- or late-onset Alzheimer's disease is unknown.
Radiological studies have also provided evidence for abnormal network activity in Alzheimer's disease. Hypometabolism visualized by positron-emission tomography or single-photon-emission computed tomography and atrophy visualized by magnetic resonance imaging (MRI) are particularly prominent in posterior components of the 'default network'20, 64
(). These alterations may reflect overall decreases in neuronal and synaptic activity but could also result from intermittent excesses in excitatory neuronal activity, which are often associated with decreased rather than increased cerebral metabolism65
. Consistent with the latter possibility, functional MRI (fMRI) studies have revealed aberrant increases in default network activity during memory encoding in subjects with Alzheimer's disease11
Radiological evidence for aberrant activity in neuronal networks of humans with Alzheimer’s disease