Early dopamine disruption in the entorhinal cortex of a knock-in model of Alzheimer's disease.

The entorhinal cortex (EC) is a critical brain area for memory formation, while also the region exhibiting the earliest histological and functional alterations in Alzheimer's disease (AD). The EC thus has been long hypothesized as one of the originating brain areas of AD pathophysiology, although circuit mechanisms causing its selective vulnerability remain poorly understood. We found that dopamine neurons projecting their axons to the lateral EC (LEC), critical for memory formation in healthy brains, become dysfunctional and cause memory impairments in early AD brains. In amyloid precursor protein knock-in mice with associative memory impairment, LEC dopamine activity and associative memory encoding of LEC layer 2/3 neurons were disrupted in parallel from the early pathological stage. Optogenetic reactivation of LEC dopamine fibers, as well as L- DOPA treatment, rescued associative learning behavior. These results suggest that dysfunction of LEC-projecting dopamine neurons underlies memory impairment in AD from early stages, pointing to a need for clinical investigation of LEC dopamine in AD patients.

Intrinsic Connectivity Identifies the Hippocampus as a Main Crossroad between Alzheimer’s and Semantic Dementia-Targeted Networks

Disrupted Place Cell Remapping and Impaired Grid Cells in a Knockin Model of Alzheimer's Disease

BackgroundDisturbances in clock genes affect almost all patients with Alzheimer’s disease (AD), as evidenced by their altered sleep/wake cycle, thermoregulation, and exacerbation of cognitive impairment. As microglia-mediated neuroinflammation proved to be a driver of AD rather than a result of the disease, in this study, we evaluated the relationship between clock gene disturbance and neuroinflammation in microglia and their contribution to the onset of AD.MethodsIn this study, the expression of clock genes and inflammatory-related genes was examined in MACS microglia isolated from 2-month-old amyloid precursor protein knock-in (APP-KI) and wild-type (WT) mice using cap analysis gene expression (CAGE) deep sequencing and RT-PCR. The effects of clock gene disturbance on neuroinflammation and relevant memory changes were examined in 2-month-old APP-KI and WT mice after injection with SR9009 (a synthetic agonist for REV-ERB). The microglia morphology was studied by staining, neuroinflammation was examined by Western blotting, and cognitive changes were examined by Y-maze and novel object recognition tests.ResultsCLOCK/BMAL1-driven transcriptional negative feedback loops were impaired in the microglia from 2-month-old APP-KI mice. Pro-inflammatory genes in microglia isolated from APP-KI mice were significantly higher than those isolated from WT mice at Zeitgeber time 14. The expression of pro-inflammatory genes was positively associated with NF-κB activation and negatively associated with the BMAL1 expression. SR9009 induced the activation of microglia, the increased expression of pro-inflammatory genes, and cognitive decline in 2-month-old APP-KI mice.ConclusionClock gene disturbance in microglia is involved in the early onset of AD through the induction of chronic neuroinflammation, which may be a new target for preventing or slowing AD.

Clinical evidence suggests that the entorhinal cortex is a primary brain area triggering memory impairments in Alzheimer’s disease (AD), but the underlying brain circuit mechanisms remain largely unclear. In healthy brains, sharp-wave ripples (SWRs) in the hippocampus and entorhinal cortex play a critical role in memory consolidation. We tested SWRs in the MEC layers 2/3 of awake amyloid precursor protein knock-in (APP-KI) mice, recorded simultaneously with SWRs in the hippocampal CA1. We found that MEC→CA1 coordination of SWRs, found previously in healthy brains, was disrupted in APP-KI mice even at a young age before the emergence of spatial memory impairments. Intriguingly, long-duration SWRs critical for memory consolidation were mildly diminished in CA1, although SWR density and amplitude remained intact. Our results point to SWR incoordination in the entorhinal-hippocampal circuit as an early network symptom that precedes memory impairment in AD.

Depression is one of the most common neuropsychiatric disorders in Alzheimer's disease (AD).To evaluate whether depression exacerbates verbal and non-verbal memory impairment in early AD patients.The study compared the performance of 23 patients who received a diagnosis of AD, with or without depression, 15 patients with unipolar major depression (UD) and 20 healthy control subjects (HS) on memory tasks (recall and recognition) for words, abstract designs and position. AD patients were stratified into two groups, according to the presence or absence of depression, well matched on clinical and sociodemographic characteristics.Patients with AD scored significantly lower than HS and UD groups on verbal memory measures. However, the recognition was the only non-verbal memory measure that discriminated significantly between AD and UD groups. The AD groups (with or without depression) did not show any significant differences on memory performance.Depression is associated with significant memory impairment in non-demented patients. The presence of depression did not increase memory impairment in AD patients.

The entorhinal cortex (EC) has bidirectional connections with the hippocampus and plays a critical role in memory formation and retrieval. EC is one of the most vulnerable regions in the brain in early stages of Alzheimer’s disease (AD), a neurodegenerative disease with progressive memory impairments. Accumulating evidence from healthy behaving animals indicates gamma oscillations (30–100 Hz) as critical for mediating interactions in the circuit between EC and hippocampus. However, it is still unclear whether gamma oscillations have causal relationship with memory impairment in AD. Here we provide the first evidence that in vivo gamma oscillations in the EC are impaired in an AD mouse model. Cross-frequency coupling of gamma (30–100 Hz) oscillations to theta oscillations was reduced in the medial EC of anesthetized amyloid precursor protein knock-in (APP-KI) mice. Phase locking of spiking activity of layer II/III pyramidal cells to the gamma oscillations was significantly impaired. These data indicate that the neural circuit activities organized by gamma oscillations were disrupted in the medial EC of AD mouse model, and point to gamma oscillations as one of possible mechanisms for cognitive dysfunction in AD patients.

Sex- and age-specific modulation of brain GABA levels in a mouse model of Alzheimer's disease

Blocking the NR2B in the hippocampal dentate gyrus reduced the spatial memory deficits and apoptosis through the PERK-CHOP pathway in a rat model of sporadic Alzheimer's disease.

The One Card Learning Test (OCL80) from the Cogstate Brief Battery—a digital cognitive test used both in-person and remotely in clinical trials and in healthcare contexts to inform health decisions—has shown high sensitivity to changes in memory in early Alzheimer's disease (AD). However, recent studies suggest that OCL sensitivity to memory impairment in symptomatic AD is not as strong as that for other standardized assessments of memory. This study aimed to improve the sensitivity of the OCL80 to AD-related memory impairment by reducing the test difficultly (i.e., OCL48). Experiment 1 showed performance in healthy adults improved on the OCL48 while the pattern separation operations that constrain performance on the OCL80 were retained. Experiment 2 showed repeated administration of the OCL48 at short retest intervals did not induce ceiling or practice effects. Experiment 3 showed that the sensitivity of the OCL48 to AD-related memory impairment (Glass's Δ = 3.11) was much greater than the sensitivity of the OCL80 (Glass's Δ = 1.94). Experiment 4 used data from a large group of cognitively normal older adults to calibrate performance scores between the OCL80 and OCL48 using equipercentile equating. Together these results showed the OCL48 to be a valid and reliable test of learning with greater sensitivity to memory impairment in AD than the OCL80.

Alzheimer's disease (AD) is a chronic degenerative disease of the central nervous system and the most common dementia type in elderly people. N-myc downstream-regulated gene 2 (NDRG2), a cell stress response gene, is primarily expressed in astrocytes in mammalian brains. The hippocampal protein levels of NDRG2 in AD patients were significantly higher than those in healthy peers. However, whether the increase in NDRG2 is involved in the development of AD or is an endogenous protective response initiated by stress remains unknown. Here, we investigated the roles of NDRG2 in the development of memory impairment in AD using mouse models established by amyloid β injection or crossing of APP/PS1 mice. We found that NDRG2 deficiency worsened the memory impairment in AD mice. In addition, NDRG2 deletion induced downregulation of the proteasome functional subunit PSMB6 in AD mice. These findings suggest that NDRG2 is an endogenous neuroprotectant that participates in the pathological course of waste-clearing impairment and memory damage in AD. NDRG2 may be a therapeutic target for the intervention of AD memory degradation.

Reshaping the gut microbiota: A novel oppinion of Eucommiae cortex polysaccharide alleviate learning and memory impairments in Alzheimer’s disease

Memory impairment is the salient feature of Alzheimer's disease (AD) and is presumed to relate to hippocampal pathology. Other regions, however, such as posterior cingulate and adjacent association cortices, are...

Astrocytic urea cycle detoxifies Aβ-derived ammonia while impairing memory in Alzheimer’s disease

Protein kinase Mzeta (PKMzeta), an atypical protein kinase C (PKC) isoform, plays a key role in the maintenance of long-term potentiation (LTP), a persistent enhancement of AMPA receptor-mediated synaptic transmission, as well as in the persistence of memory in Drosophila. Because memory impairment in Alzheimer disease (AD) has been attributed to disruption of synaptic plasticity, we investigated the expression and distribution of PKMzeta in this disorder. We found that PKMzeta accumulated in neurofibrillary tangles (NFTs), whereas conventional and novel PKC isoforms did not. Unlike tau, which is present in all NFTs regardless of location, PKMzeta was found in a subset of NFTs restricted to limbic or medial temporal lobe structures (i.e. hippocampal formation, entorhinal cortex, and amygdala), areas implicated in memory loss in AD. Interestingly, PKMzeta was not identified in any NFTs in control brains derived from 6 elderly individuals without known cognitive impairment. In medial temporal lobe structures in AD, PKMzeta also occurred within abnormal neurites expressing MAP2, GluR1 and GluR2 as well as in perisomatic granules expressing GluR1 and GluR2, suggesting that aggregation of PKMzeta disrupts glutamatergic synaptic transmission. Together, these findings suggest a link between PKMzeta-mediated synaptic plasticity and memory impairment in AD.