The comorbidity of HIV-associated neurocognitive disorders and Alzheimer's disease: a foreseeable medical challenge in post-HAART era

Abstract

Although the introduction of highly active antiretroviral therapy (HAART) has led to a strong reduction of HIV-associated dementia (HAD) incidence, the prevalence of minor HIV-1-associated neurocognitive disorder (HAND) is rising among AIDS patients. HAART medication has shifted neuropathology from a subacute encephalitic condition to a subtle neurodegenerative process involving synaptic and dendritic degeneration, particularly of hippocampal neurons that are spared prior to HAART medication. Considerable neuroinflammation coupled with mononuclear phagocyte activation is present in HAART-medicated brains, particularly in the hippocampus. Accumulating evidence suggests that the resultant elevated secretion of pro-inflammatory cytokines such as interferon-gamma, tumor necrosis factor-alpha, and interleukin-1beta can increase amyloid-beta peptide (Abeta) generation and reduce Abeta clearance. Recent advancements in Alzheimer's disease (AD) research identified Abeta biogenesis and clearance venues that are potentially influenced by HIV viral infection, providing new insights into beta-amyloidosis segregation in HIV patients. Our study suggests enhanced beta-amyloidosis in ART-treated HAD and HIV-associated encephalitis brains and suppression of Abeta clearance by viral infection of human primary macrophages. A growing awareness of potential convergent mechanisms leading to neurodegeneration shared by HIV and Abeta points to a significant chance of comorbidity of AD and HAND in senile HIV patients, which calls for a need of basic studies.

Figure 1. Enhanced β-amyloid depositions in HIVE brains

Anti-Aβ polyclonal antibody immunostaining of HIV-seronegative (A–B), HIVE (C–F) and AD (G–H) brains. Aβ–immunoreactive plaques were found in HIVE brains (asterisk, D), resembling those found in AD brain (asterisks, H). Intracellular Aβ immunoreactivity was observed in HIV-seronegative, HIVE and AD brains (arrows, B, D and H). Perivascular amyloid deposition was evident in HIVE brains (arrowhead, F). Original magnification, panels A, C, E, and G ×200, B, D, F and H ×400)

Figure 2. Proposed mechanisms leading to enhanced intraneuronal and perivascular β-amyloid depositions in HIVE brains

Activated microglia secreted elevated levels of proinflammatory cytokines (IL1-β, TNF-α, IFN-γ) that can up-regulate BACE1 and APP expression in neurons, resulting in increased Aβ generation. HIV viral protein Tat can be up-taken via LRP into neurons where it can inhibit Neprilysin activity, blocking Aβ degradation. The reduced secretion of anti-inflammatory cytokines (IL-4 and IL-10) also contributes to impaired Aβ degradation. Accelerated perivascular Aβ deposition is a consequence of impaired efflux of Aβ into plasma, and/or inhibition of perivascular Aβ degrading enzymes by viral proteins.

Figure 3. Impaired fibrillar Aβ degradation in HIV-infected human macrophages

Human monocyte-derived macrophages (MDM) were infected with HIV-1 YU-2 (0.1pg p24/cell) or uninfected, and 3 day post infection subjected to pulse-labeling with 1.0 µM ¹²⁵I-labeled fibrillar Aβ42 for 1h at 37° C. The cells were washed out and chased for different time points as indicated in graph, when media were collected and fractionated with trichloroacetic acid (TCA) into TCA-soluble fraction containing degraded Aβ42 and TCA-insoluble fraction containing aggregated Aβ42 as described (Yuyama et al. 2008). HIV infection results in intracellular Aβ retention (A), significant reduction in Aβ degradation (B) and a concomitant increase of Aβ aggregation in extracellular space (C). *** denotes p<0.001 against control group at respective time points as determined by two-way repeated measurement ANOVA and Bonferroni post tests.

Figure 4. Proposed mechanisms leading to impaired intra-macrophage Aβ degradation and facilitated extracelluar Aβ fibrillogenesis

Phagocytosed Aβ fibrils can be retrograde transported into aggresome and then refolding occurs with the help of chaperone molecules such as Hsp70; later they can be degraded by IDE or lysosomal enzymes, or excytosed. Endocytosed Aβ fibrils can also be degraded via endosome-lysosome pathway. HIV might impair Aβ fibrils degradation in macrophage through elevating TNF-α and IFN-γ (inhibitory for Aβ fibrils degradation), decreasing IL-4 and IL-10 (stimulatory for Aβ fibrils degradation), and blocking endosome-lysosomal pathway, raising a possibility that Aβ may be co-leased with virions into extracelluar space where it can serve as a seed for fibrillogenesis.