Accumulation of toxic protein aggregates-amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles-is the pathological hallmark of Alzheimer disease (AD). Aβ accumulation has been hypothesized to result from an imbalance between Aβ production and clearance; indeed, Aβ clearance seems to be impaired in both early and late forms of AD. To develop efficient strategies to slow down or halt AD, it is critical to understand how Aβ is cleared from the brain. Extracellular Aβ deposits can be removed from the brain by various clearance systems, most importantly, transport across the blood-brain barrier. Findings from the past few years suggest that astroglial-mediated interstitial fluid (ISF) bulk flow, known as the glymphatic system, might contribute to a larger portion of extracellular Aβ (eAβ) clearance than previously thought. The meningeal lymphatic vessels, discovered in 2015, might provide another clearance route. Because these clearance systems act together to drive eAβ from the brain, any alteration to their function could contribute to AD. An understanding of Aβ clearance might provide strategies to reduce excess Aβ deposits and delay, or even prevent, disease onset. In this Review, we describe the clearance systems of the brain as they relate to proteins implicated in AD pathology, with the main focus on Aβ.

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Clearance systems in the brain—implications for Alzheimer disease

Accumulating data from the clinical research support that the core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers amyloid-β (Aβ42), total tau (T-tau), and phosphorylated tau (P-tau) reflect key elements of AD pathophysiology. Importantly, a large number of clinical studies very consistently show that these biomarkers contribute with diagnostically relevant information, also in the early disease stages. Recent technical developments have made it possible to measure these biomarkers using fully automated assays with high precision and stability. Standardization efforts have given certified reference materials for CSF Aβ42, with the aim to harmonize results between assay formats that would allow for uniform global reference limits and cut-off values. These encouraging developments have led to that the core AD CSF biomarkers have a central position in the novel diagnostic criteria for the disease and in the recent National Institute on Aging and Alzheimer's Association biological definition of AD. Taken together, this progress will likely serve as the basis for a more general introduction of these diagnostic tests in clinical routine practice. However, the heterogeneity of pathology in late-onset AD calls for an expansion of the AD CSF biomarker toolbox with additional biomarkers reflecting additional aspects of AD pathophysiology. One promising candidate is the synaptic protein neurogranin that seems specific for AD and predicts future rate of cognitive deterioration. Further, recent studies bring hope for easily accessible and cost-effective screening tools in the early diagnostic evaluation of patients with cognitive problems (and suspected AD) in primary care. In this respect, technical developments with ultrasensitive immunoassays and novel mass spectrometry techniques give promise of biomarkers to monitor brain amyloidosis (the Aβ42/40 or APP669-711/Aβ42 ratios) and neurodegeneration (tau and neurofilament light proteins) in plasma samples, but future studies are warranted to validate these promising results further.

https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.12816

Biomarkers for Alzheimer's disease: current status and prospects for the future.

Synaptic loss is the major neurobiological substrate of cognitive dysfunction in Alzheimer’s disease (AD). Synaptic failure is an early event in the pathogenesis that is clearly detectable already in patients with mild cognitive impairment (MCI), a prodromal state of AD. It progresses during the course of AD and in most early stages involves mechanisms of compensation before reaching a stage of decompensated function. This dynamic process from an initially reversible functionally responsive stage of down-regulation of synaptic function to stages irreversibly associated with degeneration might be related to a disturbance of structural brain self-organization and involves morphoregulatory molecules such as the amyloid precursor protein. Further, recent evidence suggests a role for diffusible oligomers of amyloid β in synaptic dysfunction. To form synaptic connections and to continuously re-shape them in a process of ongoing structural adaptation, neurons must permanently withdraw from the cell cycle. Previously, we formulated the hypothesis that differentiated neurons after having withdrawn from the cell cycle are able to use molecular mechanisms primarily developed to control proliferation alternatively to control synaptic plasticity. The existence of these alternative effector pathways within neurons might put them at risk of erroneously converting signals derived from plastic synaptic changes into the program of cell cycle activation, which subsequently leads to cell death. The molecular mechanisms involved in cell cycle activation might, thus, link aberrant synaptic changes to cell death.

Synaptic degeneration in Alzheimer’s disease

Alzheimer's disease: connecting findings from graph theoretical studies of brain networks

The objective of our research was to determine synaptic protein levels in brain specimens from AD subjects and age-matched control subjects. Further, to determine whether presynaptic or postsynaptic compartments of neurons are preferentially affected in AD patients, we studied 3 presynaptic vesicle proteins (synaptotagmin, synaptophysin, and Rab 3A), 2 synaptic membrane proteins (Gap 43 and synaptobrevin), and 2 postsynaptic proteins (neurogranin and synaptopodin) in specimens from AD and age-matched control brains. Two brain regions--the frontal and parietal cortices--were assessed for protein levels by immunoblotting analysis. We found a loss of both presynaptic vesicle proteins and postsynaptic proteins in all brain specimens from AD patients compared to those from age-matched control subjects. Further, we found that the loss of synaptic proteins was more severe in the frontal cortex brain specimens than in the parietal cortex brain specimens from the AD subjects compared to those from the control subjects, suggesting that the frontal brain may be critical for synaptic function in AD. Using immunohistochemistry techniques, we also determined the distribution pattern of all synaptic proteins in both the frontal and parietal cortices brain specimens from control subjects. Of the 7 synaptic proteins studied, the presynaptic proteins synaptophysin and rab 3A and the postsynaptic protein synaptopodin were the most down-regulated. Our study suggests that postsynaptic proteins and presynaptic proteins are important for synaptic function and may be related to cognitive impairments in AD.

Differential loss of synaptic proteins in Alzheimer's disease: implications for synaptic dysfunction.

Alzheimer's disease (AD) is characterised by an increased number of senile plaques (SP) and neuroflbrillary tangles (NFT) as compared with that found in non-demented individuals of the same age, and a marked degeneration and loss of synapses. One of the main risk-factors for the disorder is inheritance of the apolipoprotein E4 (ApoE4) allele. To further study the relation between these pathogenetic substrates for AD, we quantified the synaptic vesicle membrane protein rab3a in brain tissue from 19 patients with AD and 9 age-matched control subjects. Rab3a levels were reduced in AD, both in the hippocampus (60% of control level, p < 0.0001), and in the frontal cortex (68% of control level, p < 0.01), but not in the cerebellum (92% of control level). Within the AD group, lower rab3a levels were found both with increasing duration and severity of dementia. These findings further support that synaptic pathology is closely correlated to the clinical dementia in AD. In contrast, no significant correlations were found between SP counts and duration or severity of dementia, while higher NFT counts in the frontal cortex were found with increasing severity of dementia (r=0.54, p < 0.05). There were no significant correlations between the rab3a level and SP or NFT counts, and by immunohistochemistry, reduced rab3a immunostaining was found throughout the neuropil in AD brain, without relation to SP or NFT. These findings suggest that the synaptic pathology in AD is not closely related to the presence of SP and NFT. No significant differences in rab3a levels were found in any brain region between AD patients possessing different numbers of the ApoE4 allele, suggesting that, although ApoE4 is a risk factor for earlier development of AD, the degree of synaptic pathology does not differ between patients with or without the ApoE4 allele.

I. Alafuzoff

Papers

Synaptic pathology in Alzheimer's disease: relation to severity of dementia, but not to senile plaques, neurofibrillary tangles, or the ApoE4 allele.